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1
Hijazi, Mohamad Ali, André Gessner, and Nahed El-Najjar. "Repurposing of Chronically Used Drugs in Cancer Therapy: A Chance to Grasp." Cancers 15, no. 12 (June 15, 2023): 3199. http://dx.doi.org/10.3390/cancers15123199.
Повний текст джерелаАнотація:
Despite the advancement in drug discovery for cancer therapy, drug repurposing remains an exceptional opportunistic strategy. This approach offers many advantages (faster, safer, and cheaper drugs) typically needed to overcome increased challenges, i.e., side effects, resistance, and costs associated with cancer therapy. However, not all drug classes suit a patient’s condition or long-time use. For that, repurposing chronically used medications is more appealing. This review highlights the importance of repurposing anti-diabetic and anti-hypertensive drugs in the global fight against human malignancies. Extensive searches of all available evidence (up to 30 March 2023) on the anti-cancer activities of anti-diabetic and anti-hypertensive agents are obtained from multiple resources (PubMed, Google Scholar, ClinicalTrials.gov, Drug Bank database, ReDo database, and the National Institutes of Health). Interestingly, more than 92 clinical trials are evaluating the anti-cancer activity of 14 anti-diabetic and anti-hypertensive drugs against more than 15 cancer types. Moreover, some of these agents have reached Phase IV evaluations, suggesting promising official release as anti-cancer medications. This comprehensive review provides current updates on different anti-diabetic and anti-hypertensive classes possessing anti-cancer activities with the available evidence about their mechanism(s) and stage of development and evaluation. Hence, it serves researchers and clinicians interested in anti-cancer drug discovery and cancer management.
2
Wahedi, Hussain Mustatab, and Deeba Amraiz. "Repurposing of Antiviral Drugs for Covid-19 Therapy." Life and Science 1, supplement (December 23, 2020): 10. http://dx.doi.org/10.37185/lns.1.1.151.
Повний текст джерелаАнотація:
Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome-associated coronavirus 2 (SARS- CoV-2) is one of the biggest health challenges across the globe ever since its eruption in late 2019. Novelty, contagiousness, and lethality of the virus demand the expedited production of potential therapeutic agents and strategies against it. Since no COVID-19 specific drug is available yet, it persists a crucial challenge to determine what therapeutic strategies should be adopted for the treatment of coronavirus patients. Until there is any specific drug for COVID-19, repurposing of the existing FDA-approved drugs is the most suitable approach to treat the severely ill patients of COVID-19. This review will summarize the existing antiviral drugs being repurposed and probed for their potential as effective anti-COVID-19 drugs all over the world.
3
Wu, King-Chuen, Kai-Sheng Liao, Li-Ren Yeh, and Yang-Kao Wang. "Drug Repurposing: The Mechanisms and Signaling Pathways of Anti-Cancer Effects of Anesthetics." Biomedicines 10, no. 7 (July 4, 2022): 1589. http://dx.doi.org/10.3390/biomedicines10071589.
Повний текст джерелаАнотація:
Cancer is one of the leading causes of death worldwide. There are only limited treatment strategies that can be applied to treat cancer, including surgical resection, chemotherapy, and radiotherapy, but these have only limited effectiveness. Developing a new drug for cancer therapy is protracted, costly, and inefficient. Recently, drug repurposing has become a rising research field to provide new meaning for an old drug. By searching a drug repurposing database ReDO_DB, a brief list of anesthetic/sedative drugs, such as haloperidol, ketamine, lidocaine, midazolam, propofol, and valproic acid, are shown to possess anti-cancer properties. Therefore, in the current review, we will provide a general overview of the anti-cancer mechanisms of these anesthetic/sedative drugs and explore the potential underlying signaling pathways and clinical application of these drugs applied individually or in combination with other anti-cancer agents.
4
Ramachandran, Sharavan, and Sanjay K. Srivastava. "Repurposing Pimavanserin, an Anti-Parkinson Drug for Pancreatic Cancer Therapy." Molecular Therapy - Oncolytics 19 (December 2020): 19–32. http://dx.doi.org/10.1016/j.omto.2020.08.019.
Повний текст джерела
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Khan, Raheel, Harras Khan, Yassen Abdullah, and Q. Ping Dou. "Feasibility of Repurposing Clioquinol for Cancer Therapy." Recent Patents on Anti-Cancer Drug Discovery 15, no. 1 (May 13, 2020): 14–31. http://dx.doi.org/10.2174/1574892815666200227090259.
Повний текст джерелаАнотація:
Background: Cancer is a prevalent disease in the world and is becoming more widespread as time goes on. Advanced and more effective chemotherapeutics need to be developed for the treatment of cancer to keep up with this prevalence. Repurposing drugs is an alternative to discover new chemotherapeutics. Clioquinol is currently being studied for reposition as an anti-cancer drug. Objective: This study aimed to summarize the anti-cancer effects of clioquinol and its derivatives through a detailed literature and patent review and to review their potential re-uses in cancer treatment. Methods: Research articles were collected through a PubMed database search using the keywords “Clioquinol” and “Cancer.” The keywords “Clioquinol Derivatives” and “Clioquinol Analogues” were also used on a PubMed database search to gather research articles on clioquinol derivatives. Patents were gathered through a Google Patents database search using the keywords “Clioquinol” and “Cancer.” Results: Clioquinol acts as a copper and zinc ionophore, a proteasome inhibitor, an anti-angiogenesis agent, and is an inhibitor of key signal transduction pathways responsible for its growth-inhibitory activity and cytotoxicity in cancer cells preclinically. A clinical trial conducted by Schimmer et al., resulted in poor outcomes that prompted studies on alternative clioquinol-based applications, such as new combinations, new delivery methods, or new clioquinol-derived analogues. In addition, numerous patents claim alternative uses of clioquinol for cancer therapy. Conclusion: Clioquinol exhibits anti-cancer activities in many cancer types, preclinically. Low therapeutic efficacy in a clinical trial has prompted new studies that aim to discover more effective clioquinol- based cancer therapies.
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Ajetunmobi, Olabayo H., Gina Wall, Bruna Vidal Bonifacio, Lucero A. Martinez Delgado, Ashok K. Chaturvedi, Laura K. Najvar, Floyd L. Wormley, et al. "High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against Candida albicans and Candida auris Biofilms." Journal of Fungi 9, no. 9 (August 27, 2023): 879. http://dx.doi.org/10.3390/jof9090879.
Повний текст джерелаАнотація:
Candidiasis is one of the most frequent nosocomial infections affecting an increasing number of at-risk patients. Candida albicans remains the most frequent causative agent of candidiasis, but, in the last decade, C. auris has emerged as a formidable multi-drug-resistant pathogen. Both species are fully capable of forming biofilms, which contribute to resistance, increasing the urgency for new effective antifungal therapies. Repurposing existing drugs could significantly accelerate the development of novel therapies against candidiasis. Here, we have screened the Repurposing Hub library from the Broad Institute, containing over 6000 compounds, in search for inhibitors of C. albicans and C. auris biofilm formation. The primary screen identified 57 initial hits against C. albicans and 33 against C. auris. Confirmatory concentration-dependent assays were used to validate the activity of the initial hits and, at the same time, establish their anti-biofilm potency. Based on these results, ebselen, temsirolimus, and compound BAY 11-7082 emerged as the leading repositionable compounds. Subsequent experiments established their spectrum of antifungal activity against yeasts and filamentous fungi. In addition, their in vivo activity was examined in the murine models of hematogenously disseminated C. albicans and C. auris infections. Although promising, further in vitro and in vivo studies are needed to confirm their potential use for the therapy of candidiasis and possibly other fungal infections.
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Vatter, Tatjana, Lukas Klumpp, Katrin Ganser, Nicolai Stransky, Daniel Zips, Franziska Eckert, and Stephan M. Huber. "Against Repurposing Methadone for Glioblastoma Therapy." Biomolecules 10, no. 6 (June 17, 2020): 917. http://dx.doi.org/10.3390/biom10060917.
Повний текст джерелаАнотація:
Methadone, which is used as maintenance medication for outpatient treatment of opioid dependence or as an analgesic drug, has been suggested by preclinical in vitro and mouse studies to induce cell death and sensitivity to chemo- or radiotherapy in leukemia, glioblastoma, and carcinoma cells. These data together with episodical public reports on long-term surviving cancer patients who use methadone led to a hype of methadone as an anti-cancer drug in social and public media. However, clinical evidence for a tumoricidal effect of methadone is missing and prospective clinical trials, except in colorectal cancer, are not envisaged because of the limited preclinical data available. The present article reviews the pharmacokinetics, potential molecular targets, as well as the evidence for a tumoricidal effect of methadone in view of the therapeutically achievable doses in the brain. Moreover, it provides original in vitro data showing that methadone at clinically relevant concentrations fails to impair clonogenicity or radioresistance of glioblastoma cells.
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Peyclit, Lucie, Hanane Yousfi, Jean-Marc Rolain, and Fadi Bittar. "Drug Repurposing in Medical Mycology: Identification of Compounds as Potential Antifungals to Overcome the Emergence of Multidrug-Resistant Fungi." Pharmaceuticals 14, no. 5 (May 20, 2021): 488. http://dx.doi.org/10.3390/ph14050488.
Повний текст джерелаАнотація:
Immunodepression, whether due to HIV infection or organ transplantation, has increased human vulnerability to fungal infections. These conditions have created an optimal environment for the emergence of opportunistic infections, which is concomitant to the increase in antifungal resistance. The use of conventional antifungal drugs as azoles and polyenes can lead to clinical failure, particularly in immunocompromised individuals. Difficulties related to treating fungal infections combined with the time required to develop new drugs, require urgent consideration of other therapeutic alternatives. Drug repurposing is one of the most promising and rapid solutions that the scientific and medical community can turn to, with low costs and safety advantages. To treat life-threatening resistant fungal infections, drug repurposing has led to the consideration of well-known and potential molecules as a last-line therapy. The aim of this review is to provide a summary of current antifungal compounds and their main resistance mechanisms, following by an overview of the antifungal activity of non-traditional antimicrobial drugs. We provide their eventual mechanisms of action and the synergistic combinations that improve the activity of current antifungal treatments. Finally, we discuss drug repurposing for the main emerging multidrug resistant (MDR) fungus, including the Candida auris, Aspergillus or Cryptococcus species.
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Doumat, George, Darine Daher, Morgan Bou Zerdan, Nasri Nasra, Hisham F. Bahmad, Monica Recine, and Robert Poppiti. "Drug Repurposing in Non-Small Cell Lung Carcinoma: Old Solutions for New Problems." Current Oncology 30, no. 1 (January 5, 2023): 704–19. http://dx.doi.org/10.3390/curroncol30010055.
Повний текст джерелаАнотація:
Lung cancer is the second most common cancer and the leading cause of cancer-related deaths in 2022. The majority (80%) of lung cancer cases belong to the non-small cell lung carcinoma (NSCLC) subtype. Despite the increased screening efforts, the median five-year survival of metastatic NSCLC remains low at approximately 3%. Common treatment approaches for NSCLC include surgery, multimodal chemotherapy, and concurrent radio and chemotherapy. NSCLC exhibits high rates of resistance to treatment, driven by its heterogeneity and the plasticity of cancer stem cells (CSCs). Drug repurposing offers a faster and cheaper way to develop new antineoplastic purposes for existing drugs, to help overcome therapy resistance. The decrease in time and funds needed stems from the availability of the pharmacokinetic and pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved drugs to be repurposed. This review provides a synopsis of the drug-repurposing approaches and mechanisms of action of potential candidate drugs used in treating NSCLC, including but not limited to antihypertensives, anti-hyperlipidemics, anti-inflammatory drugs, anti-diabetics, and anti-microbials.
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Rivas, Sarah, Vaidya Govindarajan, Mynor Mendez Valdez, John Heiss, and Ashish Shah. "EXTH-34. ANTI-RETROVIRAL REPURPOSING FOR TREATMENT OF GLIOBLASTOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii216—vii217. http://dx.doi.org/10.1093/neuonc/noac209.832.
Повний текст джерелаАнотація:
Abstract Glioblastoma (GBM) is a WHO grade IV glioma whose heterogeneous nature and stem-like features contribute to resistance to conventional chemotherapeutics. Previously, antiretrovirals have been proposed as anti-neoplastic agents, but their clinical efficacy is limited. With the advent of modern anti-retroviral and combinatorial therapy, we sought to repurpose FDA-approved anti-retroviral drugs for glioblastoma. Here, we performed an unbiased screen of 16 antiretrovirals in 40 glioma cell lines using DEPMap for drug repositioning. We identified six potential antiretrovirals among several drug classes with significant anti-glioma activity: abacavir (ABC), lamivudine (LMV), raltegravir (RLT), darunavir (DAR), indinavir (IND), and etravirine (ETV). We validated the effects of six antiretrovirals on patient-derived GBM neurospheres (GBM28 and GBM43) and established glioma cell line (A172). The non-nucleoside reverse transcriptase inhibitor (ETV) had the lowest effective IC50 in chemoresistant PDX GBM neurospheres (15uM) and A172 cells (2.7uM). Synergy assessment of ETV with standard of care temozolomide (TMZ) demonstrated that these drugs work independently of one another (Bliss score of -0.39 and -0.83 in GBM 28 and GBM 43, respectively). In addition, we investigated ETV effect on stemness features and human endogenous retroviral elements. Western blot, immunofluorescence and qPCR showed a decrease in the stemness markers, OCT-4, and HERV-K env expression. Reverse transcriptase levels decreased significantly after sublethal ETV treatment (5uM) for 48 hours in the stem-like GBMNS but not in adherent A172 cells. Overall, several antiretroviral drugs could be repositioned for glioblastoma therapy. Given its ideal therapeutic index and ability to penetrate the blood-brain barrier, ETV may be a promising candidate for future clinical trials in neuro-oncology.
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Puccetti, Matteo, Claudio Costantini, Maurizio Ricci, and Stefano Giovagnoli. "Tackling Immune Pathogenesis of COVID-19 through Molecular Pharmaceutics." Pharmaceutics 13, no. 4 (April 5, 2021): 494. http://dx.doi.org/10.3390/pharmaceutics13040494.
Повний текст джерелаАнотація:
An increasing number of clinical studies worldwide are investigating the repurposing of antiviral, immune-modulatory, and anti-inflammatory agents to face the coronavirus disease-19 (COVID-19) pandemic. Nevertheless, few effective therapies exist to prevent or treat COVID-19, which demands increased drug discovery and repurposing efforts. In fact, many currently tested drugs show unknown efficacy and unpredictable drug interactions, such that interventions are needed to guarantee access to effective and safe medicines. Anti-inflammatory therapy has proven to be effective in preventing further injury in COVID-19 patients, but the benefit comes at a cost, as targeting inflammatory pathways can imply an increased risk of infection. Thus, optimization of the risk/benefit ratio is required in the anti-inflammatory strategy against COVID-19, which accounts for drug formulations and delivery towards regionalization and personalization of treatment approaches. In this perspective, we discuss how better knowledge of endogenous immunomodulatory pathways may optimize the clinical use of novel and repurposed drugs against COVID-19 in inpatient, outpatient, and home settings through innovative drug discovery, appropriate drug delivery systems and dedicated molecular pharmaceutics.
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Torralba, Manuel, Rossella Farra, Marianna Maddaloni, Mario Grassi, Barbara Dapas, and Gabriele Grassi. "Drugs Repurposing in High-Grade Serous Ovarian Cancer." Current Medicinal Chemistry 27, no. 42 (December 16, 2020): 7222–33. http://dx.doi.org/10.2174/0929867327666200713190520.
Повний текст джерелаАнотація:
Background: Ovary Carcinoma (OC) is the most lethal gynecological neoplasm due to the late diagnoses and to the common development of resistance to platinum-based chemotherapy. Thus, novel therapeutic approaches are urgently required. In this regard, the strategy of drug repurposing is becoming attractive. By this approach, the effectiveness of a drug originally developed for another indication is tested in a different pathology. The advantage is that data about pharmacokinetic properties and toxicity are already available. Thus, in principle, it is possible to reduce research costs and to speed up drug usage/marketing. Results: Here, some noticeable examples of repurposed drugs for OC, such as amiodarone, ruxolitinib, statins, disulfiram, ormeloxifenem, and Quinacrine, are reported. Amiodarone, an antiarrhythmic agent, has shown promising anti-OC activity, although the systemic toxicity should not be neglected. The JAK inhibitor, Ruxolitinib, may be employed particularly in coadministration with standard OC therapy as it synergistically interacts with platinum-based drugs. Particularly interesting is the use of statin which represent one of the most commonly administered drugs in aged population to treat hypercholesterolemia. Disulfiram, employed in the treatment of chronic alcoholism, has shown anti-OC properties. Ormeloxifene, commonly used for contraception, seems to be promising, especially due to the negligible side effects. Finally, Quinacrine used as an antimicrobial and anti-inflammatory drug, is able to downregulate OC cell growth and promote cell death. Conclusion: Whereas further testing in patients are necessary to better clarify the therapeutic potential of repurposed drugs for OC, it is believed that their use, better if combined with OC targeted delivery systems, can significantly contribute to the development of novel and effective anti-OC treatments.
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Tilija Pun, Nirmala, and Chul-Ho Jeong. "Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance." Pharmaceuticals 14, no. 5 (May 16, 2021): 470. http://dx.doi.org/10.3390/ph14050470.
Повний текст джерелаАнотація:
Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations.
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Meng, Xin, and Ye Wang. "Drug Repurposing for Influenza Virus Polymerase Acidic (PA) Endonuclease Inhibitor." Molecules 26, no. 23 (December 2, 2021): 7326. http://dx.doi.org/10.3390/molecules26237326.
Повний текст джерелаАнотація:
Drug repurposing can quickly and effectively identify novel drug repurposing opportunities. The PA endonuclease catalytic site has recently become regarded as an attractive target for the screening of anti-influenza drugs. PA N-terminal (PAN) inhibitor can inhibit the entire PA endonuclease activity. In this study, we screened the effectivity of PAN inhibitors from the FDA database through in silico methods and in vitro experiments. PAN and mutant PAN-I38T were chosen as virtual screening targets for overcoming drug resistance. Gel-based PA endonuclease analysis determined that the drug lifitegrast can effectively inhibit PAN and PAN-I38T, when the IC50 is 32.82 ± 1.34 μM and 26.81 ± 1.2 μM, respectively. Molecular docking calculation showed that lifitegrast interacted with the residues around PA or PA-I38 T’s active site, occupying the catalytic site pocket. Both PAN/PAN-I38T and lifitegrast can acquire good equilibrium in 100 ns molecular dynamic simulation. Because of these properties, lifitegrast, which can effectively inhibit PA endonuclease activity, was screened through in silico and in vitro research. This new research will be of significance in developing more effective and selective drugs for anti-influenza therapy.
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Ezquerra-Aznárez, José Manuel, Pedro E. Almeida da Silva, and José A. Aínsa. "Overcoming the Prokaryote/Eukaryote Barrier in Tuberculosis Treatment: A Prospect for the Repurposing and Use of Antiparasitic Drugs." Microorganisms 9, no. 11 (November 11, 2021): 2335. http://dx.doi.org/10.3390/microorganisms9112335.
Повний текст джерелаАнотація:
Antimicrobial resistance, the so-called silent pandemic, is pushing industry and academia to find novel antimicrobial agents with new mechanisms of action in order to be active against susceptible and drug-resistant microorganisms. In the case of tuberculosis, the need of novel anti-tuberculosis drugs is specially challenging because of the intricate biology of its causative agent, Mycobacterium tuberculosis. The repurposing of medicines has arisen in recent years as a fast, low-cost, and efficient strategy to identify novel biomedical applications for already approved drugs. This review is focused on anti-parasitic drugs that have additionally demonstrated certain levels of anti-tuberculosis activity; along with this, natural products with a dual activity against parasites and against M. tuberculosis are discussed. A few clinical trials have tested antiparasitic drugs in tuberculosis patients, and have revealed effective dose and toxicity issues, which is consistent with the natural differences between tuberculosis and parasitic infections. However, through medicinal chemistry approaches, derivatives of drugs with anti-parasitic activity have become successful drugs for use in tuberculosis therapy. In summary, even when the repurposing of anti-parasitic drugs for tuberculosis treatment does not seem to be an easy job, it deserves attention as a potential contributor to fuel the anti-tuberculosis drug pipeline.
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Wang, Fei, and Gabriele Multhoff. "Repurposing Cannabidiol as a Potential Drug Candidate for Anti-Tumor Therapies." Biomolecules 11, no. 4 (April 15, 2021): 582. http://dx.doi.org/10.3390/biom11040582.
Повний текст джерелаАнотація:
In recent years, evidence has accumulated that cannabinoids—especially the non-psychoactive compound, cannabidiol (CBD)—possess promising medical and pharmacological activities that might qualify them as potential anti-tumor drugs. This review is based on multiple studies summarizing different mechanisms for how CBD can target tumor cells including cannabinoid receptors or other constituents of the endocannabinoid system, and their complex activation of biological systems that results in the inhibition of tumor growth. CBD also participates in anti-inflammatory activities which are related to tumor progression, as demonstrated in preclinical models. Although the numbers of clinical trials and tested tumor entities are limited, there is clear evidence that CBD has anti-tumor efficacy and is well tolerated in human cancer patients. In summary, it appears that CBD has potential as a neoadjuvant and/or adjuvant drug in therapy for cancer.
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Fiscon, Giulia, Federica Conte, Lorenzo Farina, and Paola Paci. "SAveRUNNER: A network-based algorithm for drug repurposing and its application to COVID-19." PLOS Computational Biology 17, no. 2 (February 5, 2021): e1008686. http://dx.doi.org/10.1371/journal.pcbi.1008686.
Повний текст джерелаАнотація:
The novelty of new human coronavirus COVID-19/SARS-CoV-2 and the lack of effective drugs and vaccines gave rise to a wide variety of strategies employed to fight this worldwide pandemic. Many of these strategies rely on the repositioning of existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we presented a new network-based algorithm for drug repositioning, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), which predicts drug–disease associations by quantifying the interplay between the drug targets and the disease-specific proteins in the human interactome via a novel network-based similarity measure that prioritizes associations between drugs and diseases locating in the same network neighborhoods. Specifically, we applied SAveRUNNER on a panel of 14 selected diseases with a consolidated knowledge about their disease-causing genes and that have been found to be related to COVID-19 for genetic similarity (i.e., SARS), comorbidity (e.g., cardiovascular diseases), or for their association to drugs tentatively repurposed to treat COVID-19 (e.g., malaria, HIV, rheumatoid arthritis). Focusing specifically on SARS subnetwork, we identified 282 repurposable drugs, including some the most rumored off-label drugs for COVID-19 treatments (e.g., chloroquine, hydroxychloroquine, tocilizumab, heparin), as well as a new combination therapy of 5 drugs (hydroxychloroquine, chloroquine, lopinavir, ritonavir, remdesivir), actually used in clinical practice. Furthermore, to maximize the efficiency of putative downstream validation experiments, we prioritized 24 potential anti-SARS-CoV repurposable drugs based on their network-based similarity values. These top-ranked drugs include ACE-inhibitors, monoclonal antibodies (e.g., anti-IFNγ, anti-TNFα, anti-IL12, anti-IL1β, anti-IL6), and thrombin inhibitors. Finally, our findings were in-silico validated by performing a gene set enrichment analysis, which confirmed that most of the network-predicted repurposable drugs may have a potential treatment effect against human coronavirus infections.
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Pfab, Christina, Luisa Schnobrich, Samir Eldnasoury, André Gessner, and Nahed El-Najjar. "Repurposing of Antimicrobial Agents for Cancer Therapy: What Do We Know?" Cancers 13, no. 13 (June 26, 2021): 3193. http://dx.doi.org/10.3390/cancers13133193.
Повний текст джерелаАнотація:
The substantial costs of clinical trials, the lengthy timelines of new drug discovery and development, along the high attrition rates underscore the need for alternative strategies for finding quickly suitable therapeutics agents. Given that most approved drugs possess more than one target tightly linked to other diseases, it encourages promptly testing these drugs in patients. Over the past decades, this has led to considerable attention for drug repurposing, which relies on identifying new uses for approved or investigational drugs outside the scope of the original medical indication. The known safety of approved drugs minimizes the possibility of failure for adverse toxicology, making them attractive de-risked compounds for new applications with potentially lower overall development costs and shorter development timelines. This latter case is an exciting opportunity, specifically in oncology, due to increased resistance towards the current therapies. Indeed, a large body of evidence shows that a wealth of non-cancer drugs has beneficial effects against cancer. Interestingly, 335 drugs are currently being evaluated in different clinical trials for their potential activities against various cancers (Redo database). This review aims to provide an extensive discussion about the anti-cancer activities exerted by antimicrobial agents and presents information about their mechanism(s) of action and stage of development/evaluation.
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Pacios, Olga, Lucia Blasco, Inès Bleriot, Laura Fernandez-Garcia, Mónica González Bardanca, Antón Ambroa, María López, German Bou, and Maria Tomás. "Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases." Antibiotics 9, no. 2 (February 6, 2020): 65. http://dx.doi.org/10.3390/antibiotics9020065.
Повний текст джерелаАнотація:
Antibiotic failure is one of the most worrying health problems worldwide. We are currently facing an international crisis with several problematic facets: new antibiotics are no longer being discovered, resistance mechanisms are occurring in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria are hampering the successful treatment of infections. In this context, new anti-infectious strategies against multidrug-resistant (MDR) and persistent bacteria, as well as the rescue of Food and Drug Administration (FDA)-approved compounds (drug repurposing), are being explored. Among the highlighted new anti-infectious strategies, in this review, we focus on antimicrobial peptides, anti-virulence compounds, phage therapy, and new molecules. As drugs that are being repurposed, we highlight anti-inflammatory compounds, anti-psychotics, anti-helminthics, anti-cancerous drugs, and statins.
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Schloer, Sebastian, Jonas Goretzko, and Ursula Rescher. "Repurposing Antifungals for Host-Directed Antiviral Therapy?" Pharmaceuticals 15, no. 2 (February 10, 2022): 212. http://dx.doi.org/10.3390/ph15020212.
Повний текст джерелаАнотація:
Because of their epidemic and pandemic potential, emerging viruses are a major threat to global healthcare systems. While vaccination is in general a straightforward approach to prevent viral infections, immunization can also cause escape mutants that hide from immune cell and antibody detection. Thus, other approaches than immunization are critical for the management and control of viral infections. Viruses are prone to mutations leading to the rapid emergence of resistant strains upon treatment with direct antivirals. In contrast to the direct interference with pathogen components, host-directed therapies aim to target host factors that are essential for the pathogenic replication cycle or to improve the host defense mechanisms, thus circumventing resistance. These relatively new approaches are often based on the repurposing of drugs which are already licensed for the treatment of other unrelated diseases. Here, we summarize what is known about the mechanisms and modes of action for a potential use of antifungals as repurposed host-directed anti-infectives for the therapeutic intervention to control viral infections.
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Stenvang, Jan, Christine Hjorth Andreassen, and Nils Brünner. "Screening of 129 FDA approved anti-cancer drugs in colorectal cancer cell lines resistant to oxaliplatin or irinotecan (SN38)." Journal of Clinical Oncology 35, no. 4_suppl (February 1, 2017): 642. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.642.
Повний текст джерелаАнотація:
642 Background: In metastatic colorectal cancer (mCRC) only 3 cytotoxic drugs (oxaliplatin, irinotecan and fluorouracil (5-FU)) are approved and the first and second line response rates are about 50% and 10-15%, respectively. Thus, new treatment options are needed. Novel anti-cancer drug candidates are primarily tested in an environment of drug resistance and the majority of novel drug candidates fail during clinical development. Therefore, “repurposing” of drugs has emerged as a promising strategy to apply established drugs in novel indications. The aim of this project was to screen established anti-cancer drugs to identify candidates for testing in mCRC patients relapsing on standard therapy. Methods: We applied 3 parental (drug sensitive) CRC cell lines (HCT116, HT29 and LoVo) and for each cell line also an oxaliplatin and irinotecan (SN38) resistant cell line. We obtained 129 FDA approved anti-cancer drugs from the Developmental Therapeutics Program (DTP) at the National Cancer Institute (NCI) ( https://dtp.cancer.gov/ ). The parental HT29 cell line and the drug resistant sublines HT29-SN38 and HT29-OXPT were exposed to 3 concentrations of each of the anti-cancer drugs. The effect on cell viability was analyzed by MTT assays. Nine of the drugs were analyzed for effect in the LoVo and HCT116 and the SN38- and oxaliplatin-resistant derived cell lines. Results: None of the drugs caused evident differential response between the resistant and sensitive cells or between the SN38 and oxaliplatin resistant cells. The screening confirmed the resistance as the cells displayed resistance to drugs in the same class as the one they were made resistant to. Of the drugs, 45 decreased cell viability in the HT29 parental and oxaliplatin- or SN-38 resistant cell lines. Nine drugs were tested in all nine CRC cell lines and eight decrease cell viability in the nine cell lines. These included drugs in different classes such as epigenetic drugs, antibiotics, mitotic inhibitors and targeted therapies. Conclusions: This study revealed several possible new “repurposing” drugs for CRC therapy, by showing that 45 FDA-approved anti-cancer drugs decrease cell viability in CRC cell lines with acquired drug resistance.
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Chittepu, Veera C. S. R., Poonam Kalhotra, Tzayhri Osorio-Gallardo, Tzayhri Gallardo-Velázquez, and Guillermo Osorio-Revilla. "Repurposing of FDA-Approved NSAIDs for DPP-4 Inhibition as an Alternative for Diabetes Mellitus Treatment: Computational and in Vitro Study." Pharmaceutics 11, no. 5 (May 17, 2019): 238. http://dx.doi.org/10.3390/pharmaceutics11050238.
Повний текст джерелаАнотація:
A drug repurposing strategy could be a potential approach to overcoming the economic costs for diabetes mellitus (DM) treatment incurred by most countries. DM has emerged as a global epidemic, and an increase in the outbreak has led developing countries like Mexico, India, and China to recommend a prevention method as an alternative proposed by their respective healthcare sectors. Incretin-based therapy has been successful in treating diabetes mellitus, and inhibitors like sitagliptin, vildagliptin, saxagliptin, and alogliptin belong to this category. As of now, drug repurposing strategies have not been used to identify existing therapeutics that can become dipeptidyl peptidase-4 (DPP-4) inhibitors. Hence, this work presents the use of bioinformatics tools like the Activity Atlas model, flexible molecular docking simulations, and three-dimensional reference interaction site model (3D-RISM) calculations to assist in repurposing Food and Drug Administration (FDA)-approved drugs into specific nonsteroidal anti-inflammatory medications such as DPP-4 inhibitors. Initially, the Activity Atlas model was constructed based on the top scoring DPP-4 inhibitors, and then the model was used to understand features of nonsteroidal anti-inflammatory drugs (NSAIDs) as a function of electrostatic, hydrophobic, and active shape features of DPP-4 inhibition. The FlexX algorithm was used to infer protein–ligand interacting residues, and binding energy, to predict potential draggability towards the DPP-4 mechanism of action. 3D-RISM calculations on piroxicam-bound DPP-4 were used to understand the stability of water molecules at the active site. Finally, piroxicam was chosen as the repurposing drug to become a new DPP-4 inhibitor and validated experimentally using fluorescence spectroscopy assay. These findings are novel and provide new insights into the role of piroxicam as a new lead to inhibit DPP-4 and, taking into consideration the biological half-life of piroxicam, it can be proposed as a possible therapeutic strategy for treating diabetes mellitus.
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Rieber, Manuel. "Cancer Pro-oxidant Therapy Through Copper Redox Cycling: Repurposing Disulfiram and Tetrathiomolybdate." Current Pharmaceutical Design 26, no. 35 (October 16, 2020): 4461–66. http://dx.doi.org/10.2174/1381612826666200628022113.
Повний текст джерелаАнотація:
Background: Copper (Cu) is a transition metal active in Fenton redox cycling from reduced Cu+ and H2O2, to oxidized Cu2+ and the hydroxyl radical (·OH) highly reactive oxygen species (ROS). At homeostatic Cu levels, ROS promote cell proliferation, migration, angiogenesis, and wound repair. To limit ROS toxicity, cells use Cu-dependent chaperone proteins, Cu-binding ceruloplasmin, and Cu-modulated enzymes like superoxide dismutases (SOD) like SOD1 and SOD3 to scavenge excess superoxide anions which favour Cu+ reduction, and mitochondrial cytochrome c oxidase, important in aerobic energy production. Because Cu helps drive tumor cell proliferation by promoting growth factor-independent receptor tyrosine kinase signaling, and Cu-dependent MEK1 involved in oncogenic BRAF-V600E signaling, further augmenting bioavailable Cu may promote ROS overproduction, cancer progression and eventually tumor cell death. For these reasons, the following clinically approved copper chelators are being repurposed as anti-cancer agents: a) ammonium tetrathiomolybdate (TTM) used to treat Wilson’s disease (copper overload) and Menkes disease (copper deficiency); b) Disulfiram (DSF), used against alcoholism, since it inhibits Aldehyde Dehydrogenase (ALDH1) enzyme, important in ethanol detoxification, and a key target against cancer stem cells. Moreover, TTM and DSF are also relevant in cancer clinical trials, because they increase the uptake of both Cu and Platinum (Pt)-containing anti-cancer drugs, since Pt and Cu share the same CTR1 copper transporter. Purpose: The majority of reports on Cu chelators dealt separately with either TTM, DSF or others. Here, we compare in parallel, the anti-cancer efficacy of low doses of TTM and DSF, asking whether they can be synergistic or antagonistic. The relevance of their unequal ROS inducing abilities and their different behavior as ionophores is also addressed. Significance: The potential of Cu chelators as repurposed anti-cancer drugs, should be greater in patients with higher endogenous Cu levels. Since platinum and Cu share uptake receptors, the synergism by drugs containing these metals should not be under-estimated. The potential of disulfiram or its metabolically active Cu-containing form, to inhibit ALDH1-positive tumor cells is therapeutically very important.
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Gaikwad, Shreyas Ramchandra, and Sanjay K. Srivastava. "Abstract 580: A novel drug suppresses pancreatic cancer growth through immunomodulation." Cancer Research 83, no. 7_Supplement (April 4, 2023): 580. http://dx.doi.org/10.1158/1538-7445.am2023-580.
Повний текст джерелаАнотація:
Abstract Drug repurposing is an effective strategy that is being used to explore new potential treatments for various diseases. In the current study, utilizing drug repurposing approach, we have identified anti-cancer activity of an anti-parasitic compound (MB). We evaluated the anti-cancer activity of MB in pancreatic ductal adenocarcinoma (PDAC). The average IC50 of MB in several human and murine PDAC cells was 4-6µM. The mode of cell death was apoptosis and which was confirmed using Annexin-V assay. Oral administration of MB suppressed tumor growth in both human and murine subcutaneous and orthotopic models at a dose of 5mg/kg. In the syngeneic orthotopic model, MB showed immune modulation wherein it increased infiltration of CD8 T-cells in the tumor microenvironment as compared to control groups. Based on this, we combined MB with anti-PD1 therapy to evaluate the combinatorial effect. Our results showed significant PDAC tumor growth suppression when a combination of MB and anti-PD1 therapy was used in an orthotopic PDAC tumor model. In conclusion, MB has a promising anti-cancer effect against PDAC tumors and we are currently exploring the molecular mechanism of action in PDAC cell lines and also evaluating if MB has any direct effect on immune cell populations. Citation Format: Shreyas Ramchandra Gaikwad, Sanjay K. Srivastava. A novel drug suppresses pancreatic cancer growth through immunomodulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 580.
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Jang, Woo Dae, Sangeun Jeon, Seungtaek Kim, and Sang Yup Lee. "Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay." Proceedings of the National Academy of Sciences 118, no. 30 (July 7, 2021): e2024302118. http://dx.doi.org/10.1073/pnas.2024302118.
Повний текст джерелаАнотація:
The COVID-19 pandemic caused by SARS-CoV-2 is an unprecedentedly significant health threat, prompting the need for rapidly developing antiviral drugs for the treatment. Drug repurposing is currently one of the most tangible options for rapidly developing drugs for emerging and reemerging viruses. In general, drug repurposing starts with virtual screening of approved drugs employing various computational methods. However, the actual hit rate of virtual screening is very low, and most of the predicted compounds are false positives. Here, we developed a strategy for virtual screening with much reduced false positives through incorporating predocking filtering based on shape similarity and postdocking filtering based on interaction similarity. We applied this advanced virtual screening approach to repurpose 6,218 approved and clinical trial drugs for COVID-19. All 6,218 compounds were screened against main protease and RNA-dependent RNA polymerase of SARS-CoV-2, resulting in 15 and 23 potential repurposed drugs, respectively. Among them, seven compounds can inhibit SARS-CoV-2 replication in Vero cells. Three of these drugs, emodin, omipalisib, and tipifarnib, show anti-SARS-CoV-2 activities in human lung cells, Calu-3. Notably, the activity of omipalisib is 200-fold higher than that of remdesivir in Calu-3. Furthermore, three drug combinations, omipalisib/remdesivir, tipifarnib/omipalisib, and tipifarnib/remdesivir, show strong synergistic effects in inhibiting SARS-CoV-2. Such drug combination therapy improves antiviral efficacy in SARS-CoV-2 infection and reduces the risk of each drug’s toxicity. The drug repurposing strategy reported here will be useful for rapidly developing drugs for treating COVID-19 and other viruses.
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Agostini, Francesco, Anna Masato, Luigi Bubacco, and Marco Bisaglia. "Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges." International Journal of Molecular Sciences 23, no. 1 (December 30, 2021): 398. http://dx.doi.org/10.3390/ijms23010398.
Повний текст джерелаАнотація:
Parkinson disease (PD) is a severe neurodegenerative disorder that affects around 2% of the population over 65 years old. It is characterized by the progressive loss of nigrostriatal dopaminergic neurons, resulting in motor disabilities of the patients. At present, only symptomatic cures are available, without suppressing disease progression. In this frame, the anti-diabetic drug metformin has been investigated as a potential disease modifier for PD, being a low-cost and generally well-tolerated medication, which has been successfully used for decades in the treatment of type 2 diabetes mellitus. Despite the precise mechanisms of action of metformin being not fully elucidated, the drug has been known to influence many cellular pathways that are associated with PD pathology. In this review, we present the evidence in the literature supporting the neuroprotective role of metformin, i.e., autophagy upregulation, degradation of pathological α-synuclein species, and regulation of mitochondrial functions. The epidemiological studies conducted in diabetic patients under metformin therapy aimed at evaluating the correlation between long-term metformin consumption and the risk of developing PD are also discussed. Finally, we provide an interpretation for the controversial results obtained both in experimental models and in clinical studies, thus providing a possible rationale for future investigations for the repositioning of metformin for PD therapy.
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Chen, Shun-Tsung, Chien-Hung Huang, Victor C. Kok, Chi-Ying F. Huang, Jin-Shuei Ciou, Jeffrey J. P. Tsai, Nilubon Kurubanjerdjit, and Ka-Lok Ng. "Drug repurposing and therapeutic anti-microRNA predictions for inhibition of oxidized low-density lipoprotein-induced vascular smooth muscle cell-associated diseases." Journal of Bioinformatics and Computational Biology 15, no. 01 (February 2017): 1650043. http://dx.doi.org/10.1142/s0219720016500438.
Повний текст джерелаАнотація:
Drug repurposing is a new method for disease treatments, which accelerates the identification of new uses for existing drugs with minimal side effects for patients. MicroRNA-based therapeutics are a class of drugs that have been used in gene therapy following the FDA’s approval of the first anti-sense therapy. This study examines the effects of oxLDL on vascular smooth muscle cells (VSMCs) and identifies potential drugs and antimiRs for treating VSMC-associated diseases. The Connectivity Map (cMap) database is utilized to identify potential new uses of existing drugs. The success of the identifications was supported by MTT assay, clonogenic assay and clinical trial data. Specifically, 37 drugs, some of which are undergoing clinical trials, were identified. Three of the identified drugs exhibit IC50 activities. Among the 37 drugs’ targets, three differentially expressed genes (DEGs) are identified as drug targets by using both the DrugBank and the NCBI PubChem Compound databases. Also, one DEG, DNMT1, which is regulated by 17 miRNAs, where these miRNAs are potential targets for developing antimiR-based miRNA therapy, is found.
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Rana, Ritika, Ruchika Sharma та Anoop Kumar. "Repurposing of Fluvastatin Against Candida albicans CYP450 Lanosterol 14 α-demethylase, a Target Enzyme for Antifungal Therapy: An In silico and In vitro Study". Current Molecular Medicine 19, № 7 (2 серпня 2019): 506–24. http://dx.doi.org/10.2174/1566524019666190520094644.
Повний текст джерелаАнотація:
Background: The incidence of fungal infections has increased significantly. Specifically the cases of candida albicans infection are increasing day by day and their resistance to clinically approved drugs is a major concern for humans. Various classes of antifungal drugs are available in the market for the treatment of these infections but unfortunately, none of them is able to treat the infection. Objective: Thus, in the present investigation, we have repurposed the well-known drug (Fluvastatin) in the treatment of Candida albicans infections by using in silico, in vitro and ex vivo techniques. Results: Firstly, we developed and validated a simple model of CYP45014α-lanosterol demethylase of Candida albicans by using crystal structure of Mycobacterium tuberculosis (1EA1). Further, fluvastatin was docked with a validated model of CYP45014α-lanosterol demethylase and revealed good binding affinity as that of fluconazole. In vitro results (Percentage growth retardation, Fungal growth kinetics, Biofilm test and Post antifungal test) have shown good antifungal activity of fluvastatin. Finally, the results of MTT assay have shown non-cytotoxic effect of fluvastatin in murine splenocytes and thymocytes. Results: Firstly, we developed and validated a simple model of CYP45014α-lanosterol demethylase of Candida albicans by using crystal structure of Mycobacterium tuberculosis (1EA1). Further, fluvastatin was docked with a validated model of CYP45014α-lanosterol demethylase and revealed good binding affinity as that of fluconazole. In vitro results (Percentage growth retardation, Fungal growth kinetics, Biofilm test and Post antifungal test) have shown good antifungal activity of fluvastatin. Finally, the results of MTT assay have shown non-cytotoxic effect of fluvastatin in murine splenocytes and thymocytes. Conclusion: However, further in vivo studies are required to confirm the complete role of fluvastatin as an antifungal agent.
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Ahmad, Shaban. "Molecular dynamics simulation and docking analysis of NF-κB protein binding with sulindac acid". Bioinformation 18, № 3 (31 березня 2022): 170–79. http://dx.doi.org/10.6026/97320630018170.
Повний текст джерелаАнотація:
It is of interest to document the Molecular Dynamics Simulation and docking analysis of NF-κB target with sulindac sodium in combating COVID-19 for further consideration. Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) of the arylalkanoic acid class that is marketed by Merck under the brand name Clinoril. We show the binding features of sulindac sodium with NF-κB that can be useful in drug repurposing in COVID-19 therapy.
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Guarnaccia, Laura, Giovanni Marfia, Matteo Maria Masseroli, Stefania Elena Navone, Melissa Balsamo, Manuela Caroli, Silvia Valtorta, et al. "Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma." Cancers 14, no. 1 (December 27, 2021): 112. http://dx.doi.org/10.3390/cancers14010112.
Повний текст джерелаАнотація:
Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin’s potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.
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Banaś, Patryk, Kamila Abram, Justyna Adamus, Jakub Rafał Pierzchała, Katarzyna Bednarz, Natalia Sobańska, Aleksandra Paulina Banasiak, Rafał Teichman, Jakub Kasprowicz, and Michał Hyjek. "Multipotential use of an old drug, as a new solution for anticancer therapy and multidrug-resistant urinary tract infections." Journal of Education, Health and Sport 13, no. 3 (February 1, 2023): 165–74. http://dx.doi.org/10.12775/jehs.2023.13.03.024.
Повний текст джерелаАнотація:
Introduction Nitroxoline (NTX) is a well-known chemotherapeutic agent that has been used to treat urinary tract infections since the 1960s. Today, the incidence of multidrug-resistant (MDR) bacterial strains is on the rise worldwide. This has resulted in repurposing, whereby during the ongoing research on nitroxoline, the possibility of its wide use has been demonstrated, not only in treatment against resistant pathogens, but also potential broad anti-cancer applications. Aim of the study The purpose of our work was to review scientific articles and show the multi-potential - anti-pathogenic and anti-tumor use of nitroxoline. Methods and materials We reviewed the English-language literature in the PubMed database, using the key words: „Nitroxoline”, „Nitroxoline cancer”, „Nitroxoline antibacterial use” Results Analysis of studies has shown that nitroxoline, currently used in benign urinary tract infections, is also applicable in the treatment of urinary tract infections caused by multidrug-resistant bacteria (MRD). It is also active against drug-resistant fungi and mycobacteria. Repurposing has also demonstrated the anticancer effects of nitroxoline through inhibition proliferation, induction apoptosis of tumor cells and other mechanisms, making it likely that nitroxoline will be used in cancer treatment regimens in the future. Conclusion Nitroxoline has found widespread use in the treatment of urinary tract infections caused by multidrug-resistant bacteria (MRD) and by strains of resistant fungi, which in today's world are spreading and increasing their drug resistance. Repurposing has shown promising anticancer activity of nitroxoline in the treatment of urinary tract cancers and more. The data supporting the effects of nitroxoline seem promising, suggesting the rationale for future clinical trials to further our understanding of the exact mechanisms of action and use of nitroxoline in oncology treatment.
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Lee, Chiyun, and Sanjib Bhakta. "The Prospect of Repurposing Immunomodulatory Drugs for Adjunctive Chemotherapy against Tuberculosis: A Critical Review." Antibiotics 10, no. 1 (January 19, 2021): 91. http://dx.doi.org/10.3390/antibiotics10010091.
Повний текст джерелаАнотація:
Tuberculosis (TB) remains a global health emergency, with an estimated 2 billion people infected across the world, and 1.4 million people dying to this disease every year. Many aspects of the causative agent, Mycobacterium tuberculosis, make this disease difficult for healthcare and laboratory researchers to fight against, such as unique pathophysiology, latent infection and long and complex treatment regimens, thus causing patient non-compliance with the treatment. Development of new drugs is critical for tackling these problems. Repurposing drugs is a promising strategy for generating an effective drug treatment whilst circumventing many of the challenges of conventional drug development. In this regard, the incorporation of immunomodulatory drugs into the standard regimen to potentiate frontline drugs is found to be highly appealing. Drugs of diverse chemical classes and drug categories are increasingly being evidenced to possess antitubercular activity, both in vitro and in vivo. This article explores and discusses the molecular entities that have shown promise in being repurposed for use in anti-TB adjunctive therapy and aims to provide the most up-to-date picture of their progress.
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Augustin, Yolanda, Henry M. Staines, and Sanjeev Krishna. "Artemisinins as a novel anti-cancer therapy: Targeting a global cancer pandemic through drug repurposing." Pharmacology & Therapeutics 216 (December 2020): 107706. http://dx.doi.org/10.1016/j.pharmthera.2020.107706.
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Bhadra, Kakali. "A Mini Review on Molecules Inducing Caspase-Independent Cell Death: A New Route to Cancer Therapy." Molecules 27, no. 19 (September 28, 2022): 6401. http://dx.doi.org/10.3390/molecules27196401.
Повний текст джерелаАнотація:
Most anticancer treatments trigger tumor cell death through apoptosis, where initiation of proteolytic action of caspase protein is a basic need. But under certain circumstances, apoptosis is prevented by the apoptosis inhibitor proteins, survivin and Hsp70. Several drugs focusing on classical programmed death of the cell have been reported to have low anti-tumorogenic potency due to mutations in proteins involved in the caspase-dependent programmed cell death with intrinsic and extrinsic pathways. This review concentrates on the role of anti-cancer drug molecules targeting alternative pathways of cancer cell death for treatment, by providing a molecular basis for the new strategies of novel anti-cancer treatment. Under these conditions, active agents targeting alternative cell death pathways can be considered as potent chemotherapeutic drugs. Many natural compounds and other small molecules, such as inorganic and synthetic compounds, including several repurposing drugs, are reported to cause caspase-independent cell death in the system. However, few molecules indicated both caspase-dependent as well caspase-free cell death in specific cancer lines. Cancer cells have alternative methods of caspase-independent programmed cell death which are equally promising for being targeted by small molecules. These small molecules may be useful leads for rational therapeutic drug design, and can be of potential interest for future cancer-preventive strategies.
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Cabrera-Andrade, Alejandro, Andrés López-Cortés, Gabriela Jaramillo-Koupermann, Humberto González-Díaz, Alejandro Pazos, Cristian R. Munteanu, Yunierkis Pérez-Castillo, and Eduardo Tejera. "A Multi-Objective Approach for Anti-Osteosarcoma Cancer Agents Discovery through Drug Repurposing." Pharmaceuticals 13, no. 11 (November 22, 2020): 409. http://dx.doi.org/10.3390/ph13110409.
Повний текст джерелаАнотація:
Osteosarcoma is the most common type of primary malignant bone tumor. Although nowadays 5-year survival rates can reach up to 60–70%, acute complications and late effects of osteosarcoma therapy are two of the limiting factors in treatments. We developed a multi-objective algorithm for the repurposing of new anti-osteosarcoma drugs, based on the modeling of molecules with described activity for HOS, MG63, SAOS2, and U2OS cell lines in the ChEMBL database. Several predictive models were obtained for each cell line and those with accuracy greater than 0.8 were integrated into a desirability function for the final multi-objective model. An exhaustive exploration of model combinations was carried out to obtain the best multi-objective model in virtual screening. For the top 1% of the screened list, the final model showed a BEDROC = 0.562, EF = 27.6, and AUC = 0.653. The repositioning was performed on 2218 molecules described in DrugBank. Within the top-ranked drugs, we found: temsirolimus, paclitaxel, sirolimus, everolimus, and cabazitaxel, which are antineoplastic drugs described in clinical trials for cancer in general. Interestingly, we found several broad-spectrum antibiotics and antiretroviral agents. This powerful model predicts several drugs that should be studied in depth to find new chemotherapy regimens and to propose new strategies for osteosarcoma treatment.
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Rub, Abdur, Kamal Shaker, Mohammad Kashif, Mohd Arish, Abdul Aziz Bin Dukhyil, Bader Mohammed Alshehri, Mohammed A. Alaidarous, Saeed Banawas, and Khwaja Amir. "Repurposing Glyburide as Antileishmanial Agent to Fight Against Leishmaniasis." Protein & Peptide Letters 26, no. 5 (May 29, 2019): 371–76. http://dx.doi.org/10.2174/0929866526666190301114012.
Повний текст джерелаАнотація:
Background: Leishmaniasis is caused by a protozoan parasite, Leishmania. It is common in more than 98 countries throughout the world. Due to insufficient availability of antileishmanial chemotherapeutics, it is an urgent need to search for new molecules which have better efficacy, low toxicity and are available at low cost. Objectives: There is a high rate of diabetic cases throughout the world that is why we planned to test the antileishmanial activity of glyburide, an effective sugar lowering drug used for the treatment of diabetes. In this study, glyburide showed a significant decrease in the parasite growth and survival in vitro in a dose-dependent manner. Methods: Anti-leishmanial activity of glyburide was checked by culturing Leishmania donovani promastigotes in the presence of glyburide in a dose and time dependent manner. Docking study against Leishmania donovani-Trypanothione synthetase (LdTrySyn) protein was performed using Autodock Vina tool. Results: Growth reversibility assay shows that growth of treated parasite was not reversed when transferred to fresh culture media after 7 days. Moreover, docking studies show efficient interactions of glyburide with key residues in the catalytic site of Leishmania donovani- Trypanothione synthetase (LdTrySyn), a very important leishmanial enzyme involved in parasite’s survival by detoxification of Nitric Oxide (NO) species, generated by the mammalian host as a defense molecule. Thus this study proves that the drug-repurposing is a beneficial strategy for identification of new and potent antileishmanial molecules. Conclusion: The results suggest that glyburide binds to LdTrySyn and inhibits its activity which further leads to the altered parasite morphology and inhibition of parasite growth. Glyburide may also be used in combination with other anti-leishmanial drugs to potentiate the response of the chemotherapy. Overall this study provides information about combination therapy as well as a single drug treatment for the infected patients suffering from diabetes. This study also provides raw information for further in vivo disease model studies to confirm the hypothesis.
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Wang, Chih-Hung, Yi-Hsien Hsieh, Zachary M. Powers, and Cheng-Yen Kao. "Defeating Antibiotic-Resistant Bacteria: Exploring Alternative Therapies for a Post-Antibiotic Era." International Journal of Molecular Sciences 21, no. 3 (February 5, 2020): 1061. http://dx.doi.org/10.3390/ijms21031061.
Повний текст джерелаАнотація:
Antibiotics are one of the greatest medical advances of the 20th century, however, they are quickly becoming useless due to antibiotic resistance that has been augmented by poor antibiotic stewardship and a void in novel antibiotic discovery. Few novel classes of antibiotics have been discovered since 1960, and the pipeline of antibiotics under development is limited. We therefore are heading for a post-antibiotic era in which common infections become untreatable and once again deadly. There is thus an emergent need for both novel classes of antibiotics and novel approaches to treatment, including the repurposing of existing drugs or preclinical compounds and expanded implementation of combination therapies. In this review, we highlight to utilize alternative drug targets/therapies such as combinational therapy, anti-regulator, anti-signal transduction, anti-virulence, anti-toxin, engineered bacteriophages, and microbiome, to defeat antibiotic-resistant bacteria.
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Roy, L., M. Poirier, and D. Fortin. "P11.39 Chloroquine as an anti-glioblastoma therapeutic: repurposing of an old drug." Neuro-Oncology 21, Supplement_3 (August 2019): iii51—iii52. http://dx.doi.org/10.1093/neuonc/noz126.185.
Повний текст джерелаАнотація:
Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive type of primary brain tumour in adults. These tumours depict anarchic proliferation and brain infiltration as well as radio- and chemoresistant profiles. The complete surgical resection is unachievable and responses to standard therapy are transitory. Recurrence is thus inevitable and patient prognosis is generally less than 15 months. Transforming growth factor-beta (TGF-β) holds a substantial role in supporting the GBM phenotype. We showed that TGF-β 1 expression levels correlate with overall and progression-free survival in newly diagnosed GBM patient. We also observed that chloroquine (CQ) can reduce the production of TGF-β together with proliferation, invasion, radioresistance and radio-induced invasion in vitro. Unfortunately, little is known regarding the ability of CQ to penetrate the blood-brain barrier (BBB). Therefore, our objective is to determine whether intravenous (IV) or intra-arterial (IA) infusions of CQ and hydroxychloroquine (HCQ), a pharmacological analog of CQ, can yield therapeutic brain concentrations. MATERIAL AND METHODS To assess BBB penetration, the brain, plasma and cerebrospinal fluid (CSF) concentrations of CQ/HCQ were measured by LCMS/MS at different timepoints post-IV or post-IA infusions with 20 mg/kg of CQ/HCQ in tumour-free Wistar rat. For the survival studies, We implanted 10’000 F98 murin glioblastoma cells in the right putamen of Fischer rats. Ten days post-implantation, IA and IV infusion were accomplished through cannulations of the external right carotid and tail vein respectively. RESULTS With IV injections, CQ/HCQ brain concentrations 15 minutes post-injection reached 15.76 mg/g (0.18 µM) and 1.67 mg/g (0.078 µM) respectively. However, following IA infusions, we observed a 1.74 and 20.9 fold increase (20 mg/kg HCQ) as well as 7.1 and 84.7-fold-increase (20 mg/kg CQ) in contra- and ipsilateral brain concentrations respectively. Although brain concentrations gradually decreased over time post-IA infusions, the ipsilateral hemisphere CQ concentration was still 82.81 mg/g (34.52 µM) after 6 hours. Whereas plasma concentrations were very similar following IV and IA infusions, both molecules barely accumulated in the CSF and only when using IA infusions. The median survival of the control group (IA phosphate-buffered saline) and the group treated with 20 mg/kg CQ IV were 23.5 days and 24.5 days respectively. However, rats injected with 20 mg/kg CQ IA had a median survival of 28.5 days. CONCLUSION These results suggest that IA CQ could be used to abrogate the GBM phenotype. As TGF-β is associated with resistance to both radio- and chemotherapy, we plan to characterize the combination of IA infusions of CQ in combination with radiation or chemotherapy (carboplatin).
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Hendrix, Andrew S., Thomas J. Spoonmore, Aimee D. Wilde, Nicole E. Putnam, Neal D. Hammer, Daniel J. Snyder, Scott A. Guelcher, Eric P. Skaar, and James E. Cassat. "Repurposing the Nonsteroidal Anti-inflammatory Drug Diflunisal as an Osteoprotective, Antivirulence Therapy for Staphylococcus aureus Osteomyelitis." Antimicrobial Agents and Chemotherapy 60, no. 9 (June 20, 2016): 5322–30. http://dx.doi.org/10.1128/aac.00834-16.
Повний текст джерелаАнотація:
ABSTRACTStaphylococcus aureusosteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound diflunisal in limitingS. aureuscytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibitS. aureusvirulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that diflunisal potently inhibits osteoblast cytotoxicity caused byS. aureussecreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, diflunisal is uniquely potent in the inhibition of skeletal cell deathin vitro. Moreover, local delivery of diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction duringS. aureusosteomyelitisin vivo. Collectively, these data demonstrate that diflunisal potently inhibits skeletal cell death and bone destruction associated withS. aureusinfection and may therefore be a useful adjunctive therapy for osteomyelitis.
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Vogel, Jens-Uwe, Sophie Schmidt, Daniel Schmidt, Florian Rothweiler, Benjamin Koch, Patrick Baer, Holger Rabenau, et al. "The Thrombopoietin Receptor Agonist Eltrombopag Inhibits Human Cytomegalovirus Replication Via Iron Chelation." Cells 9, no. 1 (December 20, 2019): 31. http://dx.doi.org/10.3390/cells9010031.
Повний текст джерелаАнотація:
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV disease.
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Medhasi, Sadeep, Ariya Chindamporn, and Navaporn Worasilchai. "A Review: Antimicrobial Therapy for Human Pythiosis." Antibiotics 11, no. 4 (March 26, 2022): 450. http://dx.doi.org/10.3390/antibiotics11040450.
Повний текст джерелаАнотація:
Human pythiosis is associated with poor prognosis with significant mortality caused by Pythium insidiosum. Antimicrobials’ in vitro and in vivo results against P. insidiosum are inconsistent. Although antimicrobials are clinically useful, they are not likely to achieve therapeutic success alone without surgery and immunotherapy. New therapeutic options are therefore needed. This non-exhaustive review discusses the rationale antimicrobial therapy, minimum inhibitory concentrations, and efficacy of antibacterial and antifungal agents against P. insidiosum. This review further provides insight into the immunomodulating effects of antimicrobials that can enhance the immune response to infections. Current data support using antimicrobial combination therapy for the pharmacotherapeutic management of human pythiosis. Also, the success or failure of antimicrobial treatment in human pythiosis might depend on the immunomodulatory effects of drugs. The repurposing of existing drugs is a safe strategy for anti-P. insidiosum drug discovery. To improve patient outcomes in pythiosis, we suggest further research and a deeper understanding of P. insidiosum virulence factors, host immune response, and host immune system modification by antimicrobials.
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Regan-Fendt, Kelly, Ding Li, Ryan Reyes, Lianbo Yu, Nissar A. Wani, Peng Hu, Samson T. Jacob, Kalpana Ghoshal, Philip R. O. Payne, and Tasneem Motiwala. "Transcriptomics-Based Drug Repurposing Approach Identifies Novel Drugs against Sorafenib-Resistant Hepatocellular Carcinoma." Cancers 12, no. 10 (September 23, 2020): 2730. http://dx.doi.org/10.3390/cancers12102730.
Повний текст джерелаАнотація:
Objective: Hepatocellular carcinoma (HCC) is frequently diagnosed in patients with late-stage disease who are ineligible for curative surgical therapies. The majority of patients become resistant to sorafenib, the only approved first-line therapy for advanced cancer, underscoring the need for newer, more effective drugs. The purpose of this study is to expedite identification of novel drugs against sorafenib resistant (SR)-HCC. Methods: We employed a transcriptomics-based drug repurposing method termed connectivity mapping using gene signatures from in vitro-derived SR Huh7 HCC cells. For proof of concept validation, we focused on drugs that were FDA-approved or under clinical investigation and prioritized two anti-neoplastic agents (dasatinib and fostamatinib) with targets associated with HCC. We also prospectively validated predicted gene expression changes in drug-treated SR Huh7 cells as well as identified and validated the targets of Fostamatinib in HCC. Results: Dasatinib specifically reduced the viability of SR-HCC cells that correlated with up-regulated activity of SRC family kinases, its targets, in our SR-HCC model. However, fostamatinib was able to inhibit both parental and SR HCC cells in vitro and in xenograft models. Ingenuity pathway analysis of fostamatinib gene expression signature from LINCS predicted JAK/STAT, PI3K/AKT, ERK/MAPK pathways as potential targets of fostamatinib that were validated by Western blot analysis. Fostamatinib treatment reversed the expression of genes that were deregulated in SR HCC. Conclusion: We provide proof of concept evidence for the validity of this drug repurposing approach for SR-HCC with implications for personalized medicine.
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Duarte, Diana, Armando Cardoso, and Nuno Vale. "Synergistic Growth Inhibition of HT-29 Colon and MCF-7 Breast Cancer Cells with Simultaneous and Sequential Combinations of Antineoplastics and CNS Drugs." International Journal of Molecular Sciences 22, no. 14 (July 10, 2021): 7408. http://dx.doi.org/10.3390/ijms22147408.
Повний текст джерелаАнотація:
Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC50 value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC50. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer.
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Pawełczyk, Anna, and Lucjusz Zaprutko. "Anti-COVID drugs: repurposing existing drugs or search for new complex entities, strategies and perspectives." Future Medicinal Chemistry 12, no. 19 (October 2020): 1743–57. http://dx.doi.org/10.4155/fmc-2020-0204.
Повний текст джерелаАнотація:
At the end of 2019, a novel virus causing severe acute respiratory syndrome to spread globally. There are currently no effective drugs targeting SARS-CoV-2. In this study, based on the analysis of numerous references and selected methods of computational chemistry, the strategy of integrative structural modification of small molecules with antiviral activity into potential active complex molecules has been presented. Proposed molecules have been designed based on the structure of triterpene oleanolic acid and complemented by structures characteristic of selected anti-COVID therapy assisted drugs. Their pharmaceutical molecular parameters and the preliminary bioactivity were calculated and predicted. The results of the above analyses show that among the designed complex substances there are potential antiviral agents directed mainly on SARS-CoV-2.
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Suematsu, Makoto. "Can drug repurposing stop “chase and run” between aldehydes and reactive sulfur species in anti-cancer therapy?" Oncotarget 9, no. 77 (October 2, 2018): 34453–54. http://dx.doi.org/10.18632/oncotarget.26170.
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Campbell, Courtney M., Avirup Guha, Tamanna Haque, Tomas G. Neilan, and Daniel Addison. "Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review." Journal of Clinical Medicine 9, no. 9 (September 11, 2020): 2935. http://dx.doi.org/10.3390/jcm9092935.
Повний текст джерелаАнотація:
The ongoing coronavirus disease 2019 (COVID-19) pandemic has resulted in efforts to identify therapies to ameliorate adverse clinical outcomes. The recognition of the key role for increased inflammation in COVID-19 has led to a proliferation of clinical trials targeting inflammation. The purpose of this review is to characterize the current state of immunotherapy trials in COVID-19, and focuses on associated cardiotoxicities, given the importance of pharmacovigilance. The search terms related to COVID-19 were queried in ClinicalTrials.gov. A total of 1621 trials were identified and screened for interventional trials directed at inflammation. Trials (n = 226) were fully assessed for the use of a repurposed drug, identifying a total of 141 therapeutic trials using a repurposed drug to target inflammation in COVID-19 infection. Building on the results of the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial demonstrating the benefit of low dose dexamethasone in COVID-19, repurposed drugs targeting inflammation are promising. Repurposed drugs directed at inflammation in COVID-19 primarily have been drawn from cancer therapies and immunomodulatory therapies, specifically targeted anti-inflammatory, anti-complement, and anti-rejection agents. The proposed mechanisms for many cytokine-directed and anti-rejection drugs are focused on evidence of efficacy in cytokine release syndromes in humans or animal models. Anti-complement-based therapies have the potential to decrease both inflammation and microvascular thrombosis. Cancer therapies are hypothesized to decrease vascular permeability and inflammation. Few publications to date describe using these drugs in COVID-19. Early COVID-19 intervention trials have re-emphasized the subtle, but important cardiotoxic sequelae of potential therapies on outcomes. The volume of trials targeting the COVID-19 hyper-inflammatory phase continues to grow rapidly with the evaluation of repurposed drugs and late-stage investigational agents. Leveraging known clinical safety profiles and pharmacodynamics allows swift investigation in clinical trials for a novel indication. Physicians should remain vigilant for cardiotoxicity, often not fully appreciated in small trials or in short time frames.
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Chakravarty, Kaushik, Victor G. Antontsev, Maksim Khotimchenko, Nilesh Gupta, Aditya Jagarapu, Yogesh Bundey, Hypatia Hou, Neha Maharao, and Jyotika Varshney. "Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform." Molecules 26, no. 7 (March 29, 2021): 1912. http://dx.doi.org/10.3390/molecules26071912.
Повний текст джерелаАнотація:
The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca2+-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.
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Berckmans, Yani, Yannick Hoffert, Ann Vankerckhoven, Erwin Dreesen, and An Coosemans. "Drug Repurposing for Targeting Myeloid-Derived Suppressor-Cell-Generated Immunosuppression in Ovarian Cancer: A Literature Review of Potential Candidates." Pharmaceutics 15, no. 7 (June 22, 2023): 1792. http://dx.doi.org/10.3390/pharmaceutics15071792.
Повний текст джерелаАнотація:
The lethality of patients with ovarian cancer (OC) remains high. Current treatment strategies often do not lead to the desired outcome due to the development of therapy resistance, resulting in high relapse rates. Additionally, clinical trials testing immunotherapy against OC have failed to reach significant results to date. The OC tumor microenvironment and specifically myeloid-derived suppressor cells (MDSC) are known to generate immunosuppression and inhibit the anti-tumor immune response following immunotherapy treatment. Our review aims to characterize potential candidate treatments to target MDSC in OC through drug-repurposing. A literature search identified repurposable compounds with evidence of their suppressing the effect of MDSC. A total of seventeen compounds were withheld, of which four were considered the most promising. Lurbinectedin, metformin, celecoxib, and 5-azacytidine have reported preclinical effects on MDSC and clinical evidence in OC. They have all been approved for a different indication, characterizing them as the most promising candidates for repurposing to treat patients with OC.
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Vicidomini, Caterina, Valentina Roviello, and Giovanni N. Roviello. "Molecular Basis of the Therapeutical Potential of Clove (Syzygium aromaticum L.) and Clues to Its Anti-COVID-19 Utility." Molecules 26, no. 7 (March 26, 2021): 1880. http://dx.doi.org/10.3390/molecules26071880.
Повний текст джерелаАнотація:
The current COronaVIrus Disease 19 (COVID-19) pandemic caused by SARS-CoV-2 infection is enormously affecting the worldwide health and economy. In the wait for an effective global immunization, the development of a specific therapeutic protocol to treat COVID-19 patients is clearly necessary as a short-term solution of the problem. Drug repurposing and herbal medicine represent two of the most explored strategies for an anti-COVID-19 drug discovery. Clove (Syzygium aromaticum L.) is a well-known culinary spice that has been used for centuries in folk medicine in many disorders. Interestingly, traditional medicines have used clove since ancient times to treat respiratory ailments, whilst clove ingredients show antiviral and anti-inflammatory properties. Other interesting features are the clove antithrombotic, immunostimulatory, and antibacterial effects. Thus, in this review, we discuss the potential role of clove in the frame of anti-COVID-19 therapy, focusing on the antiviral, anti-inflammatory, and antithrombotic effects of clove and its molecular constituents described in the scientific literature.
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Ngidi, Nolwazi Thobeka Portia, Kgothatso Eugene Machaba, and Ndumiso Nhlakanipho Mhlongo. "In Silico Drug Repurposing Approach: Investigation of Mycobacterium tuberculosis FadD32 Targeted by FDA-Approved Drugs." Molecules 27, no. 3 (January 20, 2022): 668. http://dx.doi.org/10.3390/molecules27030668.
Повний текст джерелаАнотація:
Background: Despite the enormous efforts made towards combating tuberculosis (TB), the disease remains a major global threat. Hence, new drugs with novel mechanisms against TB are urgently needed. Fatty acid degradation protein D32 (FadD32) has been identified as a promising drug target against TB, the protein is required for the biosynthesis of mycolic acids, hence, essential for the growth and multiplication of the mycobacterium. However, the FadD32 mechanism upon the binding of FDA-approved drugs is not well established. Herein, we applied virtual screening (VS), molecular docking, and molecular dynamic (MD) simulation to identify potential FDA-approved drugs against FadD32. Methodology/Results: VS technique was found promising to identify four FDA-approved drugs (accolate, sorafenib, mefloquine, and loperamide) with higher molecular docking scores, ranging from −8.0 to −10.0 kcal/mol. Post-MD analysis showed that the accolate hit displayed the highest total binding energy of −45.13 kcal/mol. Results also showed that the accolate hit formed more interactions with FadD32 active site residues and all active site residues displayed an increase in total binding contribution. RMSD, RMSF, Rg, and DCCM analysis further supported that the presence of accolate exhibited more structural stability, lower bimolecular flexibility, and more compactness into the FadD32 protein. Conclusions: Our study revealed accolate as the best potential drug against FadD32, hence a prospective anti-TB drug in TB therapy. In addition, we believe that the approach presented in the current study will serve as a cornerstone to identifying new potential inhibitors against a wide range of biological targets.