Artykuły w czasopismach: „DRUG LEADS TARGETING”

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Zhu, W., Y. Zhang, W. Sinko, M. E. Hensler, J. Olson, K. J. Molohon, S. Lindert i in. "Antibacterial drug leads targeting isoprenoid biosynthesis". Proceedings of the National Academy of Sciences 110, nr 1 (17.12.2012): 123–28. http://dx.doi.org/10.1073/pnas.1219899110.

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Chaitanya, MVNL, Asha Jose, P. Ramalingam, SC Mandal i PNarendra Kumar. "Multi-targeting cytotoxic drug leads from mushrooms". Asian Pacific Journal of Tropical Medicine 12, nr 12 (2019): 531. http://dx.doi.org/10.4103/1995-7645.272482.

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Kumar, Bhumika, Mukesh Pandey, Faheem H. Pottoo, Faizana Fayaz, Anjali Sharma i P. K. Sahoo. "Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease". Current Pharmaceutical Design 26, nr 37 (26.10.2020): 4721–37. http://dx.doi.org/10.2174/1381612826666200128145124.

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Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

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Suresh, Amaroju, Singireddi Srinivasarao, Yogesh Mahadu Khetmalis, Shashidhar Nizalapur, Murugesan Sankaranarayanan i Kondapalli Venkata Gowri Chandra Sekhar. "Inhibitors of pantothenate synthetase of Mycobacterium tuberculosis – a medicinal chemist perspective". RSC Advances 10, nr 61 (2020): 37098–115. http://dx.doi.org/10.1039/d0ra07398a.

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Tuberculosis, leads to numerous deaths worldwide. New drug discovery strategies are need of the hour. In the current review, we focused on the discovery of new antitubercular drugs targeting pantothenate synthetase.

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Singh, Vijai, i Pallavi Somvanshi. "Targeting the Peptide Deformylase of Mycobacterium tuberculosis Leads to Drug Discovery". Letters in Drug Design & Discovery 6, nr 7 (1.10.2009): 487–93. http://dx.doi.org/10.2174/157018009789108286.

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Pal, Rahul, Saif Hameed i Zeeshan Fatima. "Iron Deprivation Affects Drug Susceptibilities of Mycobacteria Targeting Membrane Integrity". Journal of Pathogens 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/938523.

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Multidrug resistance (MDR) acquired byMycobacterium tuberculosis(MTB) through continuous deployment of antitubercular drugs warrants immediate search for novel targets and mechanisms. The ability of MTB to sense and become accustomed to changes in the host is essential for survival and confers the basis of infection. A crucial condition that MTB must surmount is iron limitation, during the establishment of infection, since iron is required by both bacteria and humans. This study focuses on how iron deprivation affects drug susceptibilities of known anti-TB drugs inMycobacterium smegmatis, a “surrogate of MTB.” We showed that iron deprivation leads to enhanced potency of most commonly used first line anti-TB drugs that could be reverted upon iron supplementation. We explored that membrane homeostasis is disrupted upon iron deprivation as revealed by enhanced membrane permeability and hypersensitivity to membrane perturbing agent leading to increased passive diffusion of drug and TEM images showing detectable differences in cell envelope thickness. Furthermore, iron seems to be indispensable to sustain genotoxic stress suggesting its possible role in DNA repair machinery. Taken together, we for the first time established a link between cellular iron and drug susceptibility of mycobacteria suggesting iron as novel determinant to combat MDR.

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Jonchere, Barbara, Jennifer Stripay, Allison Pribnow, Frederique Zindy, Jaeki Min, Burgess Freeman, Anang Shelat, Zoran Rankovic i Martine Roussel. "PDTM-02. TARGETING THE RB PATHWAY IN MEDULLOBLASTOMA". Neuro-Oncology 21, Supplement_6 (listopad 2019): vi187. http://dx.doi.org/10.1093/neuonc/noz175.778.

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Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor, is classified into four major molecularly and histopathologically distinct subgroups, among which MYC-driven Group 3 MBs confer a poor prognosis. The Cyclin D/CDK4/CDK6/RB pathway is frequently deregulated in MB leading to uncontrolled cell proliferation, but tumors express an intact RB protein (Northcott et al., Nature, 2017). Therefore, CDK4/6 inhibitor drugs offer a possible therapeutic approach to treat MBs. Because single agent therapy ultimately leads to drug resistance, we initiated in vitro combination drug screens to identify drug classes potentiating CDK4/6 inhibitors. We used Group 3 MB patient-derived orthotopic xenografts (PDOXs), a human cell line (HDMB03), and freshly dissociated tumor cells propagated only in the mouse brain. The drug screen included 90 compounds comprising targeted and cytotoxic drugs that are FDA approved or under active clinical investigation. Using a bioluminescence-based assay that measures ATP consumption (CellTiter-Glo) to evaluate the number of viable cells, these 90 compounds were screened in combination with a fixed concentration of ribociclib, one of the three FDA approved CDK4/6 inhibitors. The primary screen, carried out in HDMB03 cells, revealed several drugs with additive or synergistic potential when combined with ribociclib, including BET inhibitors, MEK inhibitors, PI3K/mTOR inhibitors and gemcitabine. We are currently evaluating the combination of brain penetrant compounds in Group 3 MB PDOXs. The identification of potent drug combinations should provide new therapeutic options for the treatment of Group 3 MB, one of the most difficult to treat.

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Ojima, Iwao. "Tumor-targeting drug delivery of chemotherapeutic agents". Pure and Applied Chemistry 83, nr 9 (24.06.2011): 1685–98. http://dx.doi.org/10.1351/pac-con-11-02-10.

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Despite the significant progress in the development of cancer detection, prevention, surgery, and therapy, there is still no common cure for this disease. In addition, the long-standing problem of chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Therefore, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, including tumor-targeting drug delivery systems (TTDDS). In general, a TTDDS consists of a tumor recognition moiety and a cytotoxic “warhead” connected through a “smart” linker to form a conjugate. When a multi-functionalized nanomaterial is used as the vehicle, a “Trojan horse” approach becomes possible for mass delivery of cytotoxic warheads to maximize the efficacy. This account presents the progress in the molecular approaches to the design and development of novel drug delivery systems for tumor-targeting chemotherapy in our laboratory.

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Srikanth A, Shivakmar T, Shankar Sheshu R i Selva kumar S. "Molecular modelling and evaluation of antihyperthyroid drug compound". International Journal of Review in Life Sciences 9, nr 4 (27.12.2019): 30–32. http://dx.doi.org/10.26452/ijrls.v9i4.1350.

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Drug targeting will play an essential function in drug discovery in the coming years, as the amount of structural records on protein targets keeps to rise. However, the conventional technique of drug discovery, primarily based upon random screening and systematic amendment of leads through medicinal chemistry strategies, will probably no longer to be deserted absolutely because it has doubtlessly vital advantages over shape-based strategies-specifically leads diagnosed in this way are unlikely to show a near resemblance to the herbal Ligand or substrate. They might also have gained in terms of patent novelty and selectivity. Such leads could then function the basis of structure-based totally, rational amendment programs, wherein their interactions with target receptors are described and improved molecules are designed. In the present study, an attempt is made to find suitable and better analogues of drugs used in the treatment of hyperthyroidism.

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Kaminska, Kamila K., Helene C. Bertrand, Hisashi Tajima, William C. Stafford, Qing Cheng, Wan Chen, Geoffrey Wells, Elias S. J. Arner i Eng-Hui Chew. "Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads". Oncotarget 7, nr 26 (24.05.2016): 40233–51. http://dx.doi.org/10.18632/oncotarget.9579.

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Qidwai, Tabish, Farrukh Jamal, Mohd Y. Khan i Bechan Sharma. "Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum". Biochemistry Research International 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/657189.

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Emergence of rapid drug resistance to existing antimalarial drugs inPlasmodium falciparumhas created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

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Skytthe, Maria K., Jonas Heilskov Graversen i Søren K. Moestrup. "Targeting of CD163+ Macrophages in Inflammatory and Malignant Diseases". International Journal of Molecular Sciences 21, nr 15 (31.07.2020): 5497. http://dx.doi.org/10.3390/ijms21155497.

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The macrophage is a key cell in the pro- and anti-inflammatory response including that of the inflammatory microenvironment of malignant tumors. Much current drug development in chronic inflammatory diseases and cancer therefore focuses on the macrophage as a target for immunotherapy. However, this strategy is complicated by the pleiotropic phenotype of the macrophage that is highly responsive to its microenvironment. The plasticity leads to numerous types of macrophages with rather different and, to some extent, opposing functionalities, as evident by the existence of macrophages with either stimulating or down-regulating effect on inflammation and tumor growth. The phenotypes are characterized by different surface markers and the present review describes recent progress in drug-targeting of the surface marker CD163 expressed in a subpopulation of macrophages. CD163 is an abundant endocytic receptor for multiple ligands, quantitatively important being the haptoglobin-hemoglobin complex. The microenvironment of inflammation and tumorigenesis is particular rich in CD163+ macrophages. The use of antibodies for directing anti-inflammatory (e.g., glucocorticoids) or tumoricidal (e.g., doxorubicin) drugs to CD163+ macrophages in animal models of inflammation and cancer has demonstrated a high efficacy of the conjugate drugs. This macrophage-targeting approach has a low toxicity profile that may highly improve the therapeutic window of many current drugs and drug candidates.

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Sharma, Charu, Bassem Sadek, Sameer N. Goyal, Satyesh Sinha, Mohammad Amjad Kamal i Shreesh Ojha. "Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development". Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–26. http://dx.doi.org/10.1155/2015/238482.

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The cannabinoid molecules are derived fromCannabis sativaplant which acts on the cannabinoid receptors types 1 and 2 (CB1and CB2) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ9-tetrahydrocannabinol mediates its action through CB1/CB2receptors. However, these synthetic basedCannabisderived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other thanCannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.

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Koch, Karen. "Silodosin — a safer alpha-blocker targeting benign prostatic hyperplasia". South African Family Practice 57, nr 5 (1.09.2015): 2. http://dx.doi.org/10.4102/safp.v57i5.4098.

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Silodosin is a specific alpha-1A receptor inhibitor newly available in South Africa. It offers a real solution to symptoms of BPH especially in those patients with moderate prostate enlargement experiencing nocturia, frequency and incomplete voiding. It can be safely used in patients who cannot tolerate non-selective alpha blockers. The main side-effect is anejaculation, but this seldom leads to drug discontinuation. The rapid action and ongoing effectiveness of the drug offers swift relief for patients.

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Dev, Rahul. "Exploring Small Heat Shock Proteins (sHSPs) for Targeting Drug Resistance in Candida albicans and other Pathogenic Fungi". Journal of Pure and Applied Microbiology 15, nr 1 (27.02.2021): 20–28. http://dx.doi.org/10.22207/jpam.15.1.42.

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Fungal infections have predominantly increased worldwide that leads to morbidity and mortality in severe cases. Invasive candidiasis and other pathogenic fungal infections are a major problem in immunocompromised individuals and post-operative patients. Increasing resistance to existing antifungal drugs calls for the identification of novel antifungal drug targets for chemotherapeutic interventions. This demand for identification and characterization of novel drug targets leads to the development of effective antifungal therapy against drug resistant fungi. Heat shock proteins (HSPs) are important for various biological processes like protein folding, posttranslational modifications, transcription, translation, and protein aggregation. HSPs are involved in maintaining homeostasis of the cell. A subgroup of HSPs is small heat shock proteins (sHSPs), which functions as cellular chaperones. They are having a significant role in the many cellular functions like development, cytoskeletal organization, apoptosis, membrane lipid polymorphism, differentiation, autophagy, in infection recognition and are major players in various stresses like osmotic stress, pH stress, etc. Studies have shown that fungal cells express increased levels of sHSPs upon antifungal drug induced stress responses. Here we review the important role of small heat shock proteins (sHSPs) in fungal diseases and their potential as antifungal targets.

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Brahmbhatt, Devarshi. "Bioadhesive drug delivery systems: Overview and recent advances". International Journal of Chemical and Life Sciences 6, nr 3 (16.06.2017): 2016. http://dx.doi.org/10.21746/ijcls.2017.3.1.

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Bio adhesive systems have gained growing interest due to its ability to localize the drug delivery along with sustained release. This leads to reduction of side-effects due to non-specific targeting. This review provides an overview of the understanding of bioadhesive drug delivery system along with the recent advances in their formulation development.

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Nie, Huifang, Xiaodong Xie, Doudou Zhang, Yu Zhou, Bifei Li, Fengqiao Li, Feiyang Li i in. "Use of lung-specific exosomes for miRNA-126 delivery in non-small cell lung cancer". Nanoscale 12, nr 2 (2020): 877–87. http://dx.doi.org/10.1039/c9nr09011h.

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Engineered exosomes have become popular drug delivery carriers for cancer treatment. Systemic injection of organotropic exosome carrier leads to efficient targeting and efficacious anti-cancer outcome.

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Zahn, Diana, Andreas Weidner, Katayoun Saatchi, Urs O. Häfeli i Silvio Dutz. "Biodegradable magnetic microspheres for drug targeting, temperature controlled drug release, and hyperthermia". Current Directions in Biomedical Engineering 5, nr 1 (1.09.2019): 161–64. http://dx.doi.org/10.1515/cdbme-2019-0041.

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AbstractMagnetic microspheres (MMS) used for magnetic drug targeting consist of magnetic nanoparticles (MNP) and a pharmaceutical agent embedded in a polymeric matrix material. The application of MNP for drug targeting enables guiding the MMS to a target area, imaging the position of the MMS with magnetic particle imaging, and finally inducing drug release. As latter takes place by degradation of the MMS or diffusion through the matrix, an increase in temperature, e.g. through magnetic hyperthermia, leads to an accelerated drug release. Here, MMS consisting of poly(lactic-coglycolic) acid (PLGA) with different monomer ratios were prepared by an oil-in-water emulsion evaporation method. The model drug Camptothecin (CPT) and magnetic multicore nanoparticles (MCNP) with a high specific heating rate were embedded into the microspheres. We obtained MMS in the preferred size range of 1 to 2 μm with a concentration of MCNP of 16wt%, a drug load of about 0.5wt% and an excellent heating performance of 161 W/gMMS. Investigations of the drug release behaviour showed an accelerated drug release when increasing the temperature from 20 °C to 37 °C or 43 °C by using a water bath. In addition, an increase in drug release of about 50% through magnetic heating of the MMS up to 44 °C compared to 37 °C was observed. By this, a magnetic hyperthermia induced CPT release from PLGA MMS is demonstrated for the very first time.

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Hu, Qi, Xiaolin Zhang, Lanlan Jia, Xueyan Zhen, Xiaoyan Pan, Xiaoyu Xie i Sicen Wang. "Engineering biomimetic graphene nanodecoys camouflaged with the EGFR/HEK293 cell membrane for targeted capture of drug leads". Biomaterials Science 8, nr 20 (2020): 5690–97. http://dx.doi.org/10.1039/d0bm00841a.

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Raj, Hans, Ankita Sharma, Shagun Sharma, Kapil Kumar Verma i Amit Chaudhary. "Mucoadhesive Microspheres: A Targeted Drug Delivery System". Journal of Drug Delivery and Therapeutics 11, nr 2-S (15.04.2021): 150–55. http://dx.doi.org/10.22270/jddt.v11i2-s.4791.

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Carrier technology is a novel and groundbreaking drug delivery system. Microspheres transmit the drug by affixing it to carrier particle-like Microspheres, Nanoparticles and Liposomes due to their smaller size and other useful properties. Mucoadhesive Microspheres are an integral component of this multi-particle drug delivery system and play an important function in the delivery of a novel drug. This drug delivery improves the therapeutic effectiveness of the drug. Mucoadhesive microspheres have a longer duration of residence at the absorption site, which leads to the accuracy of the drug targeting at the absorption site and improves the therapeutic efficacy of the drug. Mucoadhesive microspheres are formed by either systemic or local effects in gastrointestinal, oral, vaginal, nasal, rectal, ocular delivery. This is the ideal targeting device which could be done in a variety of ways. Keywords: Microspheres, Bioadhesion, Polymer, Bioavailability

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Lee, Jae-Seon, Ho Lee, Hyonchol Jang, Sang Myung Woo, Jong Bae Park, Seon-Hyeong Lee, Joon Hee Kang, Hee Yeon Kim, Jaewhan Song i Soo-Youl Kim. "Targeting Oxidative Phosphorylation Reverses Drug Resistance in Cancer Cells by Blocking Autophagy Recycling". Cells 9, nr 9 (1.09.2020): 2013. http://dx.doi.org/10.3390/cells9092013.

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The greatest challenge in cancer therapy is posed by drug-resistant recurrence following treatment. Anticancer chemotherapy is largely focused on targeting the rapid proliferation and biosynthesis of cancer cells. This strategy has the potential to trigger autophagy, enabling cancer cell survival through the recycling of molecules and energy essential for biosynthesis, leading to drug resistance. Autophagy recycling contributes amino acids and ATP to restore mTOR complex 1 (mTORC1) activity, which leads to cell survival. However, autophagy with mTORC1 activation can be stalled by reducing the ATP level. We have previously shown that cytosolic NADH production supported by aldehyde dehydrogenase (ALDH) is critical for supplying ATP through oxidative phosphorylation (OxPhos) in cancer cell mitochondria. Inhibitors of the mitochondrial complex I of the OxPhos electron transfer chain and ALDH significantly reduce the ATP level selectively in cancer cells, terminating autophagy triggered by anticancer drug treatment. With the aim of overcoming drug resistance, we investigated combining the inhibition of mitochondrial complex I, using phenformin, and ALDH, using gossypol, with anticancer drug treatment. Here, we show that OxPhos targeting combined with anticancer drugs acts synergistically to enhance the anticancer effect in mouse xenograft models of various cancers, which suggests a potential therapeutic approach for drug-resistant cancer.

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Gisbert-Garzarán, Miguel, Daniel Lozano i María Vallet-Regí. "Mesoporous Silica Nanoparticles for Targeting Subcellular Organelles". International Journal of Molecular Sciences 21, nr 24 (18.12.2020): 9696. http://dx.doi.org/10.3390/ijms21249696.

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Current chemotherapy treatments lack great selectivity towards tumoral cells, which leads to nonspecific drug distribution and subsequent side effects. In this regard, the use of nanoparticles able to encapsulate and release therapeutic agents has attracted growing attention. In this sense, mesoporous silica nanoparticles (MSNs) have been widely employed as drug carriers owing to their exquisite physico-chemical properties. Because MSNs present a surface full of silanol groups, they can be easily functionalized to endow the nanoparticles with many different functionalities, including the introduction of moieties with affinity for the cell membrane or relevant compartments within the cell, thus increasing the efficacy of the treatments. This review manuscript will provide the state-of-the-art on MSNs functionalized for targeting subcellular compartments, focusing on the cytoplasm, the mitochondria, and the nucleus.

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Rinaldetti, Sébastien, Qiong Zhou, Joshua M. Abbott, Florus C. de Jong, Hector Esquer, James C. Costello, Dan Theodorescu i Daniel V. LaBarbera. "High-Content Drug Discovery Targeting Molecular Bladder Cancer Subtypes". International Journal of Molecular Sciences 23, nr 18 (14.09.2022): 10605. http://dx.doi.org/10.3390/ijms231810605.

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Molecular subtypes of muscle-invasive bladder cancer (MIBC) display differential survival and drug sensitivities in clinical trials. To date, they have not been used as a paradigm for phenotypic drug discovery. This study aimed to discover novel subtype-stratified therapy approaches based on high-content screening (HCS) drug discovery. Transcriptome expression data of CCLE and BLA-40 cell lines were used for molecular subtype assignment in basal, luminal, and mesenchymal-like cell lines. Two independent HCSs, using focused compound libraries, were conducted to identify subtype-specific drug leads. We correlated lead drug sensitivity data with functional genomics, regulon analysis, and in-vitro drug response-based enrichment analysis. The basal MIBC subtype displayed sensitivity to HDAC and CHK inhibitors, while the luminal subtype was sensitive to MDM2 inhibitors. The mesenchymal-like cell lines were exclusively sensitive to the ITGAV inhibitor SB273005. The role of integrins within this mesenchymal-like MIBC subtype was confirmed via its regulon activity and gene essentiality based on CRISPR–Cas9 knock-out data. Patients with high ITGAV expression showed a significant decrease in the median overall survival. Phenotypic high-content drug screens based on bladder cancer cell lines provide rationales for novel stratified therapeutic approaches as a framework for further prospective validation in clinical trials.

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Acquah, Francis A., i Blaine H. M. Mooers. "Targeting RNA Structure to Inhibit Editing in Trypanosomes". International Journal of Molecular Sciences 24, nr 12 (14.06.2023): 10110. http://dx.doi.org/10.3390/ijms241210110.

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Mitochondrial RNA editing in trypanosomes represents an attractive target for developing safer and more efficient drugs for treating infections with trypanosomes because this RNA editing pathway is not found in humans. Other workers have targeted several enzymes in this editing system, but not the RNA. Here, we target a universal domain of the RNA editing substrate, which is the U-helix formed between the oligo-U tail of the guide RNA and the target mRNA. We selected a part of the U-helix that is rich in G-U wobble base pairs as the target site for the virtual screening of 262,000 compounds. After chemoinformatic filtering of the top 5000 leads, we subjected 50 representative complexes to 50 nanoseconds of molecular dynamics simulations. We identified 15 compounds that retained stable interactions in the deep groove of the U-helix. The microscale thermophoresis binding experiments on these five compounds show low-micromolar to nanomolar binding affinities. The UV melting studies show an increase in the melting temperatures of the U-helix upon binding by each compound. These five compounds can serve as leads for drug development and as research tools to probe the role of the RNA structure in trypanosomal RNA editing.

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Alirezaie Alavijeh, Ali, Mohammad Barati, Meisam Barati i Hussein Abbasi Dehkordi. "The Potential of Magnetic Nanoparticles for Diagnosis and Treatment of Cancer Based on Body Magnetic Field and Organ-on-the-Chip". Advanced Pharmaceutical Bulletin 9, nr 3 (1.08.2019): 360–73. http://dx.doi.org/10.15171/apb.2019.043.

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Cancer is an abnormal cell growth which tends to proliferate in an uncontrolled way and, in some cases, leads to metastasis. If cancer is left untreated, it can immediately cause death. The use of magnetic nanoparticles (MNPs) as a drug delivery system will enable drugs to target tissues and cell types precisely. This study describes usual strategies and consideration for the synthesis of MNPs and incorporates payload drug on MNPs. They have advantages such as visual targeting and delivering which will be discussed in this review. In addition, we considered body magnetic field to make drug delivery process more effective and safer by the application of MNPs and tumor-on-chip.

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Wang, Xiao, Wenting Zhao, Bin Wang, Wei Ding, Hao Guo, Hongyi Zhao, Jianzhou Meng i in. "Identification of inhibitors targeting polyketide synthase 13 of Mycobacterium tuberculosis as antituberculosis drug leads". Bioorganic Chemistry 114 (wrzesień 2021): 105110. http://dx.doi.org/10.1016/j.bioorg.2021.105110.

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Fu, Jia, Qianqian Jia, Peida Liang, Saisai Wang, Huaxin Zhou, Liyang Zhang, Chunlei Gao, Hong Wang, Yanni Lv i Shengli Han. "Targeting and Covalently Immobilizing the EGFR through SNAP-Tag Technology for Screening Drug Leads". Analytical Chemistry 93, nr 34 (20.08.2021): 11719–28. http://dx.doi.org/10.1021/acs.analchem.1c01664.

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Zhang, Minhua, Guangrui Luo, Yanjiao Zhou, Shaohui Wang i Zhong Zhong. "Phenotypic Screens Targeting Neurodegenerative Diseases". Journal of Biomolecular Screening 19, nr 1 (19.08.2013): 1–16. http://dx.doi.org/10.1177/1087057113499777.

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Neurodegenerative diseases affect millions of people worldwide, and the incidences increase as the population ages. Disease-modifying therapy that prevents or slows disease progression is still lacking, making neurodegenerative diseases an area of high unmet medical need. Target-based drug discovery for disease-modifying agents has been ongoing for many years, without much success due to incomplete understanding of the molecular mechanisms underlying neurodegeneration. Phenotypic screening, starting with a disease-relevant phenotype to screen for compounds that change the outcome of biological pathways rather than activities at certain specific targets, offers an alternative approach to find small molecules or targets that modulate the key characteristics of neurodegeneration. Phenotypic screens that focus on amelioration of disease-specific toxins, protection of neurons from degeneration, or promotion of neuroregeneration could be potential fertile grounds for discovering therapeutic agents for neurodegenerative diseases. In this review, we will summarize the progress of compound screening using these phenotypic-based strategies for this area, with a highlight on unique considerations for disease models, assays, and screening methodologies. We will further provide our perspectives on how best to use phenotypic screening to develop drug leads for neurodegenerative diseases.

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Belmant, Christian, Donatella Decise i Jean-Jacques Fournié. "Phosphoantigens and aminobisphosphonates: New leads targeting γδ T lymphocytes for cancer immunotherapy". Drug Discovery Today: Therapeutic Strategies 3, nr 1 (marzec 2006): 17–23. http://dx.doi.org/10.1016/j.ddstr.2006.02.001.

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Esteban-Martos, Alvaro, Ana Maria Brokate-Llanos, Luis Miguel Real, Sonia Melgar-Locatelli, Itziar de Rojas, Adriana Castro-Zavala, Maria Jose Bravo i in. "A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease". International Journal of Molecular Sciences 24, nr 15 (28.07.2023): 12079. http://dx.doi.org/10.3390/ijms241512079.

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Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer’s disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aβ1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin’s effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.

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Stephanie, Filia, Mutiara Saragih, Usman Sumo Friend Tambunan i Teruna J. Siahaan. "Structural Design and Synthesis of Novel Cyclic Peptide Inhibitors Targeting Mycobacterium tuberculosis Transcription". Life 12, nr 9 (28.08.2022): 1333. http://dx.doi.org/10.3390/life12091333.

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Tuberculosis (TB) remains one of the deadliest infectious diseases in the world. Although several established antitubercular drugs have been found, various factors obstruct efforts to combat this disease due to the existence of drug-resistance (DR) TB strains, the need for lengthy treatment, and the occurrence of side effects from drug–drug interactions. Rifampicin (RIF) is the first line of antitubercular drugs and targets RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB). Here, RIF blocks the synthesis of long RNA during transcription initiation. The efficacy of RIF is low in DR-TB strains, and the use of RIF leads to various side effects. In this study, novel cyclic peptides were computationally designed as inhibitors of MTB transcription initiation. The designed cyclic peptides were subjected to a virtual screening to generate compounds that can bind to the RIF binding site in MTB RNAP subunit β (RpoB) for obtaining a new potential TB drug with a safe clinical profile. The molecular simulations showed that the cyclic peptides were capable of binding with RpoB mutants, suggesting that they can be possibility utilized for treating DR-TB. Structural modifications were carried out by acetylation and amidation of the N- and C-terminus, respectively, to improve their plasma stability and bioavailability. The modified linear and cyclic peptides were successfully synthesized with a solid-phase peptide synthesis method using Fmoc chemistry, and they were characterized by analytical HPLC, LC-ESI-MS+, and 1H NMR.

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Bléry, Mathieu, Manel Mrabet-Kraiem, Ariane Morel, Florence Lhospice, Delphine Bregeon, Cécile Bonnafous, Laurent Gauthier i in. "Targeting MICA/B with cytotoxic therapeutic antibodies leads to tumor control". Open Research Europe 1 (27.10.2021): 107. http://dx.doi.org/10.12688/openreseurope.13314.2.

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Background: MICA and MICB are tightly regulated stress-induced proteins that trigger the immune system by binding to the activating receptor NKG2D on cytotoxic lymphocytes. MICA and MICB are highly polymorphic molecules with prevalent expression on several types of solid tumors and limited expression in normal/healthy tissues, making them attractive targets for therapeutic intervention. Methods: We have generated a series of anti-MICA and MICB cross-reactive antibodies with the unique feature of binding to the most prevalent isoforms of both these molecules. Results: The anti-MICA and MICB antibody MICAB1, a human IgG1 Fc-engineered monoclonal antibody (mAb), displayed potent antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of MICA/B-expressing tumor cells in vitro. However, it showed insufficient efficiency against solid tumors in vivo, which prompted the development of antibody-drug conjugates (ADC). Indeed, optimal tumor control was achieved with MICAB1-ADC format in several solid tumor models, including patient-derived xenografts (PDX) and carcinogen-induced tumors in immunocompetent MICAgen transgenic mice. Conclusions: These data indicate that MICA and MICB are promising targets for cytotoxic immunotherapy.

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Bléry, Mathieu, Manel Mrabet-Kraiem, Ariane Morel, Florence Lhospice, Delphine Bregeon, Cécile Bonnafous, Laurent Gauthier i in. "Targeting MICA/B with cytotoxic therapeutic antibodies leads to tumor control". Open Research Europe 1 (13.09.2021): 107. http://dx.doi.org/10.12688/openreseurope.13314.1.

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Background: MICA and MICB are tightly regulated stress-induced proteins that trigger the immune system by binding to the activating receptor NKG2D on cytotoxic lymphocytes. MICA and MICB are highly polymorphic molecules with prevalent expression on several types of solid tumors and limited expression in normal/healthy tissues, making them attractive targets for therapeutic intervention. Methods: We have generated a series of anti-MICA and MICB cross-reactive antibodies with the unique feature of binding to the most prevalent isoforms of both these molecules. Results: The anti-MICA and MICB antibody MICAB1, a human IgG1 Fc-engineered monoclonal antibody (mAb), displayed potent antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of MICA/B-expressing tumor cells in vitro. However, it showed insufficient efficiency against solid tumors in vivo, which prompted the development of antibody-drug conjugates (ADC). Indeed, optimal tumor control was achieved with MICAB1-ADC format in several solid tumor models, including patient-derived xenografts (PDX) and carcinogen-induced tumors in immunocompetent MICAgen transgenic mice. Conclusions: These data indicate that MICA and MICB are promising targets for cytotoxic immunotherapy.

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Liu, Ran, Gang Zhao, Shujun Wang, Yan Gu, Qi Han i Baoan Chen. "TfR mAb-Cross-Linked Rituximab/MTX-PEG-PLL-PLGA Drug-Loaded Nanoparticles Enhance Anticancer Action in B Lymphocytes". Journal of Nanomaterials 2019 (12.09.2019): 1–8. http://dx.doi.org/10.1155/2019/7265450.

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Nanoparticles could enhance the drug targeted to the cancer cell by the enrichment of the drug levels, which leads to the improvement of the codelivery of both drugs for an antitumor effect. In the current study, we reported an efficient, local drug-loaded delivery strategy with a nanoparticle-loaded system. After the synthesis of Rituximab/MTX-PEG-PLL-PLGA, the transferrin receptor monoantibody (TfR mAb) was subsequently cross-linked to the nanoparticles. Compared to the traditional drug, the nanoparticle-loaded system can precisely and efficiently transport the Rituximab and Methotrexate (MTX) drug into SU-DHL-4 cells, a typical kind of B lymphocytes, which can significantly increase the cell apoptosis in the SU-DHL-4 cells. Thus, the multifunctional drug-loaded nanoparticles displayed the persistent stability and precise targeting properties, which enhanced the efficiency of anticancer efficiency in B lymphocytes.

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35

Haghaei, Hossein, Somaieh Soltani, Seyedrafie Aref Hosseini, Mohammad Reza Rashidi i Saeed Karima. "Boswellic Acids as Promising Leads in Drug Development against Alzheimer’s Disease". Pharmaceutical Sciences 27, nr 1 (18.03.2020): 14–31. http://dx.doi.org/10.34172/ps.2020.25.

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Biological activity of Boswellia extract (BE) has been attributed to its main active ingredients; i.e. Boswellic acids (BAs). BE/BAs possess a promising therapeutic potential in neurodegenerative disorders; including Alzheimer's disease (AD). The multifactorial nature of AD pathophysiology necessitates the development of the disease-modifying agents (DMA). Recent multi-targeting approaches for the DMAs development have brought more attention to the plant-derived compounds regarding their better human compatibility because of their biologic origin. This review addresses the current knowledge on the anti-AD activity of BE/BAs based on the available in silico, in vitro, in vivo studies and clinical trials. The contribution of BE/BAs in inflammatory pathways, Tau and β-amyloid proteins, microtubule functions, oxidative stress, cholinesterase and diabetes/insulin pathways involved in AD have been discussed. BAs efficacy in different AD-related pathways has been confirmed in vitro and in vivo. They can be considered as valuable scaffold/lead compounds for multi-targeted DMAs in anti-AD drug discovery and development.

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Oswald, James T., Haritosh Patel, Daid Khan, Ninweh N. Jeorje, Hossein Golzar, Erin L. Oswald i Shirley Tang. "Drug Delivery Systems Using Surface Markers for Targeting Cancer Stem Cells". Current Pharmaceutical Design 26, nr 17 (7.06.2020): 2057–71. http://dx.doi.org/10.2174/1381612826666200406084900.

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The innate abilities of cancer stem cells (CSCs), such as multi-drug resistance, drug efflux, quiescence and ionizing radiation tolerance, protect them from most traditional chemotherapeutics. As a result, this small subpopulation of persistent cells leads to more aggressive and chemoresistant cancers, causing tumour relapse and metastasis. This subpopulation is differentiated from the bulk tumour population through a wide variety of surface markers expressed on the cell surface. Recent developments in nanomedicine and targeting delivery methods have given rise to new possibilities for specifically targeting these markers and preferentially eliminating CSCs. Herein, we first summarize the range of surface markers identifying CSC populations in a variety of cancers; then, we discuss recent attempts to actively target CSCs and their niches using liposomal, nanoparticle, carbon nanotube and viral formulations.

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Foulks, Jason M., K. Mark Parnell, Rebecca N. Nix, Suzanna Chau, Krzysztof Swierczek, Michael Saunders, Kevin Wright i in. "Epigenetic Drug Discovery". Journal of Biomolecular Screening 17, nr 1 (30.09.2011): 2–17. http://dx.doi.org/10.1177/1087057111421212.

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Epigenetic modification of DNA leads to changes in gene expression. DNA methyltransferases (DNMTs) comprise a family of nuclear enzymes that catalyze the methylation of CpG dinucleotides, resulting in an epigenetic methylome distinguished between normal cells and those in disease states such as cancer. Disrupting gene expression patterns through promoter methylation has been implicated in many malignancies and supports DNMTs as attractive therapeutic targets. This review focuses on the rationale of targeting DNMTs in cancer, the historical approach to DNMT inhibition, and current marketed hypomethylating therapeutics azacytidine and decitabine. In addition, we address novel DNMT inhibitory agents emerging in development, including CP-4200 and SGI-110, analogs of azacytidine and decitabine, respectively; the oligonucleotides MG98 and miR29a; and a number of reversible inhibitors, some of which appear to be selective against particular DNMT isoforms. Finally, we discuss future opportunities and challenges for next-generation therapeutics.

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Qiu, Ziyi, Zhenhua Yu, Ting Xu, Liuyou Wang, Nanxin Meng, Huawei Jin i Bingzhe Xu. "Novel Nano-Drug Delivery System for Brain Tumor Treatment". Cells 11, nr 23 (24.11.2022): 3761. http://dx.doi.org/10.3390/cells11233761.

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As the most dangerous tumors, brain tumors are usually treated with surgical removal, radiation therapy, and chemotherapy. However, due to the aggressive growth of gliomas and their resistance to conventional chemoradiotherapy, it is difficult to cure brain tumors by conventional means. In addition, the higher dose requirement of chemotherapeutic drugs caused by the blood–brain barrier (BBB) and the untargeted nature of the drug inevitably leads to low efficacy and systemic toxicity of chemotherapy. In recent years, nanodrug carriers have attracted extensive attention because of their superior drug transport capacity and easy-to-control properties. This review systematically summarizes the major strategies of novel nano-drug delivery systems for the treatment of brain tumors in recent years that cross the BBB and enhance brain targeting, and compares the advantages and disadvantages of several strategies.

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Allam, Ahmed E., Yhiya Amen, Ahmed Ashour, Hamdy K. Assaf, Heba Ali Hassan, Islam M. Abdel-Rahman, Ahmed M. Sayed i Kuniyoshi Shimizu. "In silico study of natural compounds from sesame against COVID-19 by targeting Mpro, PLpro and RdRp". RSC Advances 11, nr 36 (2021): 22398–408. http://dx.doi.org/10.1039/d1ra03937g.

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Gourley, Eric S., Xiao-Hui Liu, Jeremy D. Lamb, Hariprasad Vankayalapati, Cory L. Grand i David J. Bearss. "Targeting Pim Kinases in Hematological Malignancies." Blood 110, nr 11 (16.11.2007): 2655. http://dx.doi.org/10.1182/blood.v110.11.2655.2655.

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Abstract The three Pim kinases represent a small subfamily of serine/threonine kinases known to be involved in a number of signaling pathways as downstream effectors and potent inhibitors of apoptosis. Unlike most other kinases, Pim kinases lack a regulatory domain which means they are controlled largely at the transcriptional level and that the mRNA expression levels of Pim kinases in cells correlate with their activity. While normal expression of Pim-1 kinase is seen in cells of hematopoietic origin, examination of gene expression of Pim-1 in different malignancies using cDNA microarray analysis suggests that Pim-1 is overexpressed in a large percentage of ALL, AML, CML, DLBCL, Prostatic Adenocarcinoma, Bladder, and Oral cancers. Pim-2 is also largely expressed in ALL, AML, Squamous Cell Lung and Adenocarcinoma of the Lung while Pim-3 is restricted to Melanoma, Pancreatic Adenocarcinoma, Gastric cancers. This implicates Pim-1 and Pim-2 in the onset and progression in several of hematological malignancies and therefore they represent interesting potential targets for drug development. To evaluate the potential of Pim-1 and -2 as a drug targets we have identified and synthesized a series of Pim kinase inhibitors using our proprietary CLIMB™ drug discovery process. Through the use of CLIMB™, the published Pim-1 kinase crystal structure was used to build several models that were then used to predict potential small molecule inhibitors of Pim-1 and Pim-2 from a large virtual library. A subset of leads, based on calculated binding energies as well as additional physical chemical properties, were screened using a number of in silico physicochemical and ADMET prediction algorithms to determine which compounds were most likely to be successful in a biological context. Lead candidates were initially screened using biochemical enzyme-based and cell-based assays. Cell-based activity was determined in HEL (acute megakaryocytic leukemia), K562 (chronic myeloid leukemia), MO7e (myeloid leukemia), and other human leukemia and lymphoma cell lines. From several lead candidates a series of analogs were produced with improved inhibitory activity and pharmacokinetic characteristics. In the Pim-1 and Pim-2 in vitro kinase assay and in the cell-based assay a number of leads exhibited inhibitory activity with IC50 concentrations in the low nanomolar range. Here we present the details of the biochemical and cell-based assay results as well as the activity in tumor xenograft models of our Pim kinase inhibitors.

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Alharbi, Ahmed. "Molecular docking based design of Inhibitors for viral Non-Nucleosidase as potential anti-retroviral agents". Bioinformation 16, nr 10 (31.10.2020): 736–41. http://dx.doi.org/10.6026/97320630016736.

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Reverse Transcriptase (RT) inhibitors are highly promising agents for use as an effective anti-retroviral therapy (HAART) which is typically a combination of three or four antiretroviral drugs. We used direct drug design approach to discover new chemical entities for the target protein. The validated template of the protein targeting reverse transcriptase PDB ID 1JKH was extracted for three sites hydrophobic, steric, and electronic parameters explain the interactions at the active site by the inhibitors. We used the Zinc library of compounds to explore the possible leads for HAART through RT inhibition. We report 12 new chemical entities with possible activity against the targeted viral protein. These leads will provide new therapeutic means in antiretroviral therapy.

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Altamura, Concetta, Paola Gavazzo, Michael Pusch i Jean-François Desaphy. "Ion Channel Involvement in Tumor Drug Resistance". Journal of Personalized Medicine 12, nr 2 (3.02.2022): 210. http://dx.doi.org/10.3390/jpm12020210.

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Over 90% of deaths in cancer patients are attributed to tumor drug resistance. Resistance to therapeutic agents can be due to an innate property of cancer cells or can be acquired during chemotherapy. In recent years, it has become increasingly clear that regulation of membrane ion channels is an important mechanism in the development of chemoresistance. Here, we review the contribution of ion channels in drug resistance of various types of cancers, evaluating their potential in clinical management. Several molecular mechanisms have been proposed, including evasion of apoptosis, cell cycle arrest, decreased drug accumulation in cancer cells, and activation of alternative escape pathways such as autophagy. Each of these mechanisms leads to a reduction of the therapeutic efficacy of administered drugs, causing more difficulty in cancer treatment. Thus, targeting ion channels might represent a good option for adjuvant therapies in order to counteract chemoresistance development.

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Stofberg, Melissa Louise, Celine Caillet, Marianne de Villiers i Tawanda Zininga. "Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future". Cells 10, nr 11 (22.10.2021): 2849. http://dx.doi.org/10.3390/cells10112849.

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Malaria is still one of the major killer parasitic diseases in tropical settings, posing a public health threat. The development of antimalarial drug resistance is reversing the gains made in attempts to control the disease. The parasite leads a complex life cycle that has adapted to outwit almost all known antimalarial drugs to date, including the first line of treatment, artesunate. There is a high unmet need to develop new strategies and identify novel therapeutics to reverse antimalarial drug resistance development. Among the strategies, here we focus and discuss the merits of the development of antimalarials targeting the Heat shock protein 90 (Hsp90) due to the central role it plays in protein quality control.

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Song, Guini, Min Zhao, Hanmin Chen, Cameron Lenahan, Xiangyue Zhou, Yibo Ou i Yue He. "The Role of Nanomaterials in Stroke Treatment: Targeting Oxidative Stress". Oxidative Medicine and Cellular Longevity 2021 (17.03.2021): 1–15. http://dx.doi.org/10.1155/2021/8857486.

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Stroke has a high rate of morbidity and disability, which seriously endangers human health. In stroke, oxidative stress leads to further damage to the brain tissue. Therefore, treatment for oxidative stress is urgently needed. However, antioxidative drugs have demonstrated obvious protective effects in preclinical studies, but the clinical studies have not seen breakthroughs. Nanomaterials, with their characteristically small size, can be used to deliver drugs and have demonstrated excellent performance in treating various diseases. Additionally, some nanomaterials have shown potential in scavenging reactive oxygen species (ROS) in stroke according to the nature of nanomaterials. The drugs’ delivery ability of nanomaterials has great significance for the clinical translation and application of antioxidants. It increases drug blood concentration and half-life and targets the ischemic brain to protect cells from oxidative stress-induced death. This review summarizes the characteristics and progress of nanomaterials in the application of antioxidant therapy in stroke, including ischemic stroke, hemorrhagic stroke, and neural regeneration. We also discuss the prospect of nanomaterials for the treatment of oxidative stress in stroke and the challenges in their application, such as the toxicity and the off-target effects of nanomaterials.

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Lam, Kuen Kuen, Siew Heng Wong i Peh Yean Cheah. "Targeting the ‘Undruggable’ Driver Protein, KRAS, in Epithelial Cancers: Current Perspective". Cells 12, nr 4 (15.02.2023): 631. http://dx.doi.org/10.3390/cells12040631.

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This review summarizes recent development in synthetic drugs and biologics targeting intracellular driver genes in epithelial cancers, focusing on KRAS, and provides a current perspective and potential leads for the field. Compared to biologics, small molecule inhibitors (SMIs) readily penetrate cells, thus being able to target intracellular proteins. However, SMIs frequently suffer from pleiotropic effects, off-target cytotoxicity and invariably elicit resistance. In contrast, biologics are much larger molecules limited by cellular entry, but if this is surmounted, they may have more specific effects and less therapy-induced resistance. Exciting breakthroughs in the past two years include engineering of non-covalent KRAS G12D-specific inhibitor, probody bispecific antibodies, drug–peptide conjugate as MHC-restricted neoantigen to prompt immune response by T-cells, and success in the adoptive cell therapy front in both breast and pancreatic cancers.

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Finol-Urdaneta, Rocio K., Aleksandra Belovanovic, Milica Micic-Vicovac, Gemma K. Kinsella, Jeffrey R. McArthur i Ahmed Al-Sabi. "Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds". Marine Drugs 18, nr 3 (20.03.2020): 173. http://dx.doi.org/10.3390/md18030173.

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Toxins from marine animals provide molecular tools for the study of many ion channels, including mammalian voltage-gated potassium channels of the Kv1 family. Selectivity profiling and molecular investigation of these toxins have contributed to the development of novel drug leads with therapeutic potential for the treatment of ion channel-related diseases or channelopathies. Here, we review specific peptide and small-molecule marine toxins modulating Kv1 channels and thus cover recent findings of bioactives found in the venoms of marine Gastropod (cone snails), Cnidarian (sea anemones), and small compounds from cyanobacteria. Furthermore, we discuss pivotal advancements at exploiting the interaction of κM-conotoxin RIIIJ and heteromeric Kv1.1/1.2 channels as prevalent neuronal Kv complex. RIIIJ’s exquisite Kv1 subtype selectivity underpins a novel and facile functional classification of large-diameter dorsal root ganglion neurons. The vast potential of marine toxins warrants further collaborative efforts and high-throughput approaches aimed at the discovery and profiling of Kv1-targeted bioactives, which will greatly accelerate the development of a thorough molecular toolbox and much-needed therapeutics.

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Gao, Wei, Jin-Yong Kim, Jeffrey R. Anderson, Tatos Akopian, Seungpyo Hong, Ying-Yu Jin, Olga Kandror i in. "The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo". Antimicrobial Agents and Chemotherapy 59, nr 2 (24.11.2014): 880–89. http://dx.doi.org/10.1128/aac.04054-14.

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ABSTRACTDrug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition ofMycobacterium tuberculosisviability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity againstM. tuberculosisin vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains ofM. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition ofM. tuberculosisgrowth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistantM. tuberculosisstrains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target againstM. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development.

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Zhang, Haiping, Yang Yang, Junxin Li, Min Wang, Konda Mani Saravanan, Jinli Wei, Justin Tze-Yang Ng i in. "A novel virtual screening procedure identifies Pralatrexate as inhibitor of SARS-CoV-2 RdRp and it reduces viral replication in vitro". PLOS Computational Biology 16, nr 12 (31.12.2020): e1008489. http://dx.doi.org/10.1371/journal.pcbi.1008489.

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The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 0.008μM and 9.453 μM, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19.

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Mukherjee, Avinaba. "A Systematic Review on Parasite Induced Carcinogenesis". International Journal of Innovative Science and Research Technology 5, nr 6 (10.07.2020): 1095–99. http://dx.doi.org/10.38124/ijisrt20jun882.

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Parasitic pathogens through cross infection exert carcinogenesis in human body. The immune evasion strategy that has been adapted by several parasites is recognized to be associated with human carcinogenicity. In this review, studies have been analyzed which depicts how carcinogenicity occurs through several parasitic infection. Among the parasites that are involved toward developing carcinogenicity, Helminth is found to be dominant as per the recent studies. One reason for this that they mostly have prolonged life cycle than the other parasites, therefore more complex network through molecular endeavour has been adapted by them that would leads the host cell malignancy. This review particularly summarizes the parasites that are involved in carcinogenicity and the mechanism that they adapt to develop so. Targeting the molecules that are being modulated by parasites to trigger carcinogenesis, drug development can be done. Drug designing can also be made by targeting the parasite induced secretory molecules which mainly cross talk to develop carcinogenicity. Specially conjugated therapy of parasitic drugs with anticancer drugs that are target specific should be used at minimum doses so that to block the parasite induced carcinogenicity in host body.

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Kumar, Prateek, Deepak Kumar i Rajanish Giri. "Targeting the nsp2 Cysteine Protease of Chikungunya Virus Using FDA Approved Library and Selected Cysteine Protease Inhibitors". Pathogens 8, nr 3 (15.08.2019): 128. http://dx.doi.org/10.3390/pathogens8030128.

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Chikungunya virus (CHIKV) infection is one of the major public health concerns, leading thousands of cases every year in rural as well as urban regions of several countries worldwide, few to mention are India, Philippines, Indonesia, and also in American countries. The structural and non-structural proteins of CHIKV are structurally and functionally similar to other alphaviruses such as Sindbis virus, Venezuelan Equine Encephalitis virus. The precursor protein of non-structural proteins is cleaved by proteolytic activity of non-structural protein (nsp2). This multifunctional nsp2 carry out nucleoside-triphosphatase (NTPase) and RNA helicase activity at its N-terminal and protease activity at C-terminal that makes it primarily a drug target to inhibit CHIKV replication. Until the current date, no suitable treatment for chikungunya infection is available. The introduction of a new drug into the market is a lengthy process, therefore, drug repurposing is now familiar approach that cut off the time and cost of drug discovery. In this study, we have implemented this approach with Food and Drug Administration (FDA) approved drugs and known cysteine protease inhibitors against CHIKV nsp2 protease using structure-based drug discovery. Our extensive docking and molecular dynamics simulations studies leads to two best interacting compounds, Ribostamycin sulfate and E-64, with utmost stable complexes at active site of nsp2 protease. Therefore, these compounds could be suitable for inhibiting CHIKV protease activity, and ultimately the viral replication.

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