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1
Geraghty, Robert, Matthew Aliota, and Laurent Bonnac. "Broad-Spectrum Antiviral Strategies and Nucleoside Analogues." Viruses 13, no. 4 (April 13, 2021): 667. http://dx.doi.org/10.3390/v13040667.
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The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and SARS-CoV-2) viruses, or new strains of influenza represents significant human health threats due to the absence of available treatments. Vaccines represent a key answer to control these viruses. However, in the case of a public health emergency, vaccine development, safety, and partial efficacy concerns may hinder their prompt deployment. Thus, developing broad-spectrum antiviral molecules for a fast response is essential to face an outbreak crisis as well as for bioweapon countermeasures. So far, broad-spectrum antivirals include two main categories: the family of drugs targeting the host-cell machinery essential for virus infection and replication, and the family of drugs directly targeting viruses. Among the molecules directly targeting viruses, nucleoside analogues form an essential class of broad-spectrum antiviral drugs. In this review, we will discuss the interest for broad-spectrum antiviral strategies and their limitations, with an emphasis on virus-targeted, broad-spectrum, antiviral nucleoside analogues and their mechanisms of action.
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Tian, Wen-Jun, and Xiao-Jia Wang. "Broad-Spectrum Antivirals Derived from Natural Products." Viruses 15, no. 5 (April 30, 2023): 1100. http://dx.doi.org/10.3390/v15051100.
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Scientific advances have led to the development and production of numerous vaccines and antiviral drugs, but viruses, including re-emerging and emerging viruses, such as SARS-CoV-2, remain a major threat to human health. Many antiviral agents are rarely used in clinical treatment, however, because of their inefficacy and resistance. The toxicity of natural products may be lower, and some natural products have multiple targets, which means less resistance. Therefore, natural products may be an effective means to solve virus infection in the future. New techniques and ideas are currently being developed for the design and screening of antiviral drugs thanks to recent revelations about virus replication mechanisms and the advancement of molecular docking technology. This review will summarize recently discovered antiviral drugs, mechanisms of action, and screening and design strategies for novel antiviral agents.
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Krzyzowska, Malgorzata, Martyna Janicka, Emilia Tomaszewska, Katarzyna Ranoszek-Soliwoda, Grzegorz Celichowski, Jarosław Grobelny, and Pawel Szymanski. "Lactoferrin-Conjugated Nanoparticles as New Antivirals." Pharmaceutics 14, no. 9 (September 3, 2022): 1862. http://dx.doi.org/10.3390/pharmaceutics14091862.
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Lactoferrin is an iron-binding glycoprotein with multiple functions in the body. Its activity against a broad spectrum of both DNA and RNA viruses as well as the ability to modulate immune responses have made it of interest in the pharmaceutical and food industries. The mechanisms of its antiviral activity include direct binding to the viruses or its receptors or the upregulation of antiviral responses by the immune system. Recently, much effort has been devoted to the use of nanotechnology in the development of new antivirals. In this review, we focus on describing the antiviral mechanisms of lactoferrin and the possible use of nanotechnology to construct safe and effective new antiviral drugs.
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Ghanbari, Reza, Ali Teimoori, Anahita Sadeghi, Ashraf Mohamadkhani, Sama Rezasoltani, Ebrahim Asadi, Abolghasem Jouyban, and Susan CJ Sumner. "Existing antiviral options against SARS-CoV-2 replication in COVID-19 patients." Future Microbiology 15, no. 18 (December 2020): 1747–58. http://dx.doi.org/10.2217/fmb-2020-0120.
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COVID-19 caused by SARS-CoV-2, is an international concern. This infection requires urgent efforts to develop new antiviral compounds. To date, no specific drug in controlling this disease has been identified. Developing the new treatment is usually time consuming, therefore using the repurposing broad-spectrum antiviral drugs could be an effective strategy to respond immediately. In this review, a number of broad-spectrum antivirals with potential efficacy to inhibit the virus replication via targeting the virus spike protein (S protein), RNA-dependent RNA polymerase (RdRp), 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) that are critical in the pathogenesis and life cycle of coronavirus, have been evaluated as possible treatment options against SARS-CoV-2 in COVID-19 patients.
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Gao, Chengfeng, Chunxia Wen, Zhifeng Li, Shuhan Lin, Shu Gao, Haida Ding, Peng Zou, Zheng Xing, and Yufeng Yu. "Fludarabine Inhibits Infection of Zika Virus, SFTS Phlebovirus, and Enterovirus A71." Viruses 13, no. 5 (April 27, 2021): 774. http://dx.doi.org/10.3390/v13050774.
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Viral infections are one of the leading causes in human mortality and disease. Broad-spectrum antiviral drugs are a powerful weapon against new and re-emerging viruses. However, viral resistance to existing broad-spectrum antivirals remains a challenge, which demands development of new broad-spectrum therapeutics. In this report, we showed that fludarabine, a fluorinated purine analogue, effectively inhibited infection of RNA viruses, including Zika virus, Severe fever with thrombocytopenia syndrome virus, and Enterovirus A71, with all IC50 values below 1 μM in Vero, BHK21, U251 MG, and HMC3 cells. We observed that fludarabine has shown cytotoxicity to these cells only at high doses indicating it could be safe for future clinical use if approved. In conclusion, this study suggests that fludarabine could be developed as a potential broad-spectrum anti-RNA virus therapeutic agent.
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Vicente, Josefina, Martina Benedetti, Paula Martelliti, Luciana Vázquez, María Virginia Gentilini, Freddy Armando Peñaranda Figueredo, Mercedes Soledad Nabaes Jodar, Mariana Viegas, Andrea Alejandra Barquero, and Carlos Alberto Bueno. "The Flavonoid Cyanidin Shows Immunomodulatory and Broad-Spectrum Antiviral Properties, Including SARS-CoV-2." Viruses 15, no. 4 (April 18, 2023): 989. http://dx.doi.org/10.3390/v15040989.
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New antiviral treatments are needed to deal with the unpredictable emergence of viruses. Furthermore, vaccines and antivirals are only available for just a few viral infections, and antiviral drug resistance is an increasing concern. Cyanidin (a natural product also called A18), a key flavonoid that is present in red berries and other fruits, attenuates the development of several diseases, through its anti-inflammatory effects. Regarding its mechanism of action, A18 was identified as an IL-17A inhibitor, resulting in the attenuation of IL-17A signaling and associated diseases in mice. Importantly, A18 also inhibits the NF-κB signaling pathway in different cell types and conditions in vitro and in vivo. In this study, we report that A18 restricts RSV, HSV-1, canine coronavirus, and SARS-CoV-2 multiplication, indicating a broad-spectrum antiviral activity. We also found that A18 can control cytokine and NF-κB induction in RSV-infected cells independently of its antiviral activity. Furthermore, in mice infected with RSV, A18 not only significantly reduces viral titers in the lungs, but also diminishes lung injury. Thus, these results provide evidence that A18 could be used as a broad-spectrum antiviral and may contribute to the development of novel therapeutic targets to control these viral infections and pathogenesis.
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Tampere, Marianna, Aleksandra Pettke, Cristiano Salata, Olov Wallner, Tobias Koolmeister, Armando Cazares-Körner, Torkild Visnes, et al. "Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses." Viruses 12, no. 12 (December 10, 2020): 1423. http://dx.doi.org/10.3390/v12121423.
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Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approach for development of antiviral compounds, especially with new, unexplored viruses where knowledge of virus biology is limited. Here, we present a strategy to identify host-targeted small molecule inhibitors using an image-based phenotypic antiviral screening assay followed by extensive target identification efforts revealing altered cellular pathways upon antiviral compound treatment. The newly discovered antiviral compounds showed broad-range antiviral activity against pathogenic RNA viruses such as SARS-CoV-2, EBOV and Crimean-Congo hemorrhagic fever virus (CCHFV). Target identification of the antiviral compounds by thermal protein profiling revealed major effects on proteostasis pathways and disturbance in interactions between cellular HSP70 complex and viral proteins, illustrating the supportive role of HSP70 on many RNA viruses across virus families. Collectively, this strategy identifies new small molecule inhibitors with broad antiviral activity against pathogenic RNA viruses, but also uncovers novel virus biology urgently needed for design of new antiviral therapies.
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Lee, Choongho. "Carrageenans as Broad-Spectrum Microbicides: Current Status and Challenges." Marine Drugs 18, no. 9 (August 21, 2020): 435. http://dx.doi.org/10.3390/md18090435.
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Different kinds of red algae are enriched with chemically diverse carbohydrates. In particular, a group of sulfated polysaccharides, which were isolated from the cell walls of red algae, gained a large amount of attention due to their broad-spectrum antimicrobial activities. Within that group, carrageenans (CGs) were expected to be the first clinically applicable microbicides that could prevent various viral infections due to their superior antiviral potency and desirable safety profiles in subclinical studies. However, their anticipated beneficial effects could not be validated in human studies. To assess the value of a second attempt at pharmacologically developing CGs as a new class of preventive microbicides, all preclinical and clinical development processes of CG-based microbicides need to be thoroughly re-evaluated. In this review, the in vitro toxicities; in vivo safety profiles; and in vitro, ex vivo, and in vivo antiviral activities of CGs are summarized according to the study volume of their target viruses, which include human immunodeficiency virus, herpesviruses, respiratory viruses, human papillomavirus, dengue virus, and other viruses along with a description of their antiviral modes of action and development of antiviral resistance. This evaluation of the strengths and weaknesses of CGs will help provide future research directions that may lead to the successful development of CG-based antimicrobial prophylactics.
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de Wispelaere, Mélissanne, Margot Carocci, Dominique J. Burri, William J. Neidermyer, Calla M. Olson, Imme Roggenbach, Yanke Liang, et al. "A broad-spectrum antiviral molecule, QL47, selectively inhibits eukaryotic translation." Journal of Biological Chemistry 295, no. 6 (December 30, 2019): 1694–703. http://dx.doi.org/10.1074/jbc.ra119.011132.
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Small-molecule inhibitors of translation are critical tools to study the molecular mechanisms of protein synthesis. In this study, we sought to characterize how QL47, a host-targeted, small-molecule antiviral agent, inhibits steady-state viral protein expression. We demonstrate that this small molecule broadly inhibits both viral and host protein synthesis and targets a translation step specific to eukaryotic cells. We show that QL47 inhibits protein neosynthesis initiated by both canonical cap-driven and noncanonical initiation strategies, most likely by targeting an early step in translation elongation. Our findings thus establish QL47 as a new small-molecule inhibitor that can be utilized to probe the eukaryotic translation machinery and that can be further developed as a new therapeutic agent.
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Jones, Jeremy C., Bindumadhav M. Marathe, Christian Lerner, Lukas Kreis, Rodolfo Gasser, Philippe Noriel Q. Pascua, Isabel Najera, and Elena A. Govorkova. "A Novel Endonuclease Inhibitor Exhibits Broad-Spectrum Anti-Influenza Virus ActivityIn Vitro." Antimicrobial Agents and Chemotherapy 60, no. 9 (July 5, 2016): 5504–14. http://dx.doi.org/10.1128/aac.00888-16.
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ABSTRACTAntiviral drugs are important in preventing and controlling influenza, particularly when vaccines are ineffective or unavailable. A single class of antiviral drugs, the neuraminidase inhibitors (NAIs), is recommended for treating influenza. The limited therapeutic options and the potential risk of antiviral resistance are driving the search for additional small-molecule inhibitors that act on influenza virus proteins. The acid polymerase (PA) of influenza viruses is a promising target for new antivirals because of its essential role in initiating virus transcription. Here, we characterized a novel compound, RO-7, identified as a putative PA endonuclease inhibitor. RO-7 was effective when added before the cessation of genome replication, reduced polymerase activity in cell-free systems, and decreased relative amounts of viral mRNA and genomic RNA during influenza virus infection. RO-7 specifically inhibited the ability of the PA endonuclease domain to cleave a nucleic acid substrate. RO-7 also inhibited influenza A viruses (seasonal and 2009 pandemic H1N1 and seasonal H3N2) and B viruses (Yamagata and Victoria lineages), zoonotic viruses (H5N1, H7N9, and H9N2), and NAI-resistant variants in plaque reduction, yield reduction, and cell viability assays in Madin-Darby canine kidney (MDCK) cells with nanomolar to submicromolar 50% effective concentrations (EC50s), low toxicity, and favorable selective indices. RO-7 also inhibited influenza virus replication in primary normal human bronchial epithelial cells. Overall, RO-7 exhibits broad-spectrum activity against influenza A and B viruses in multiplein vitroassays, supporting its further characterization and development as a potential antiviral agent for treating influenza.
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Chianese, Annalisa, Carla Zannella, Alessandra Monti, Anna De Filippis, Nunzianna Doti, Gianluigi Franci, and Massimiliano Galdiero. "The Broad-Spectrum Antiviral Potential of the Amphibian Peptide AR-23." International Journal of Molecular Sciences 23, no. 2 (January 14, 2022): 883. http://dx.doi.org/10.3390/ijms23020883.
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Viral infections represent a serious threat to the world population and are becoming more frequent. The search and identification of broad-spectrum antiviral molecules is necessary to ensure new therapeutic options, since there is a limited availability of effective antiviral drugs able to eradicate viral infections, and consequently due to the increase of strains that are resistant to the most used drugs. Recently, several studies on antimicrobial peptides identified them as promising antiviral agents. In detail, amphibian skin secretions serve as a rich source of natural antimicrobial peptides. Their antibacterial and antifungal activities have been widely reported, but their exploitation as potential antiviral agents have yet to be fully investigated. In the present study, the antiviral activity of the peptide derived from the secretion of Rana tagoi, named AR-23, was evaluated against both DNA and RNA viruses, with or without envelope. Different assays were performed to identify in which step of the infectious cycle the peptide could act. AR-23 exhibited a greater inhibitory activity in the early stages of infection against both DNA (HSV-1) and RNA (MeV, HPIV-2, HCoV-229E, and SARS-CoV-2) enveloped viruses and, on the contrary, it was inactive against naked viruses (PV-1). Altogether, the results indicated AR-23 as a peptide with potential therapeutic effects against a wide variety of human viruses.
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Mese, Kemal, Oskar Bunz, Wolfram Volkwein, Sahithya P. B. Vemulapalli, Wenli Zhang, Sebastian Schellhorn, Kristin Heenemann, et al. "Enhanced Antiviral Function of Magnesium Chloride-Modified Heparin on a Broad Spectrum of Viruses." International Journal of Molecular Sciences 22, no. 18 (September 17, 2021): 10075. http://dx.doi.org/10.3390/ijms221810075.
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Previous studies reported on the broad-spectrum antiviral function of heparin. Here we investigated the antiviral function of magnesium-modified heparin and found that modified heparin displayed a significantly enhanced antiviral function against human adenovirus (HAdV) in immortalized and primary cells. Nuclear magnetic resonance analyses revealed a conformational change of heparin when complexed with magnesium. To broadly explore this discovery, we tested the antiviral function of modified heparin against herpes simplex virus type 1 (HSV-1) and found that the replication of HSV-1 was even further decreased compared to aciclovir. Moreover, we investigated the antiviral effect against the new severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and measured a 55-fold decreased viral load in the supernatant of infected cells associated with a 38-fold decrease in virus growth. The advantage of our modified heparin is an increased antiviral effect compared to regular heparin.
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Morales Vasquez, Desarey, Jun-Gyu Park, Ginés Ávila-Pérez, Aitor Nogales, Juan Carlos de la Torre, Fernando Almazan, and Luis Martinez-Sobrido. "Identification of Inhibitors of ZIKV Replication." Viruses 12, no. 9 (September 18, 2020): 1041. http://dx.doi.org/10.3390/v12091041.
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Zika virus (ZIKV) was identified in 1947 in the Zika forest of Uganda and it has emerged recently as a global health threat, with recurring outbreaks and its associations with congenital microcephaly through maternal fetal transmission and Guillain-Barré syndrome. Currently, there are no United States (US) Food and Drug Administration (FDA)-approved vaccines or antivirals to treat ZIKV infections, which underscores an urgent medical need for the development of disease intervention strategies to treat ZIKV infection and associated disease. Drug repurposing offers various advantages over developing an entirely new drug by significantly reducing the timeline and resources required to advance a candidate antiviral into the clinic. Screening the ReFRAME library, we identified ten compounds with antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV). Moreover, we showed the ability of these ten compounds to inhibit influenza A and B virus infections, supporting their broad-spectrum antiviral activity. In this study, we further evaluated the broad-spectrum antiviral activity of the ten identified compounds by testing their activity against ZIKV. Among the ten compounds, Azaribine (SI-MTT = 146.29), AVN-944 (SI-MTT = 278.16), and Brequinar (SI-MTT = 157.42) showed potent anti-ZIKV activity in post-treatment therapeutic conditions. We also observed potent anti-ZIKV activity for Mycophenolate mofetil (SI-MTT = 20.51), Mycophenolic acid (SI-MTT = 36.33), and AVN-944 (SI-MTT = 24.51) in pre-treatment prophylactic conditions and potent co-treatment inhibitory activity for Obatoclax (SI-MTT = 60.58), Azaribine (SI-MTT = 91.51), and Mycophenolate mofetil (SI-MTT = 73.26) in co-treatment conditions. Importantly, the inhibitory effect of these compounds was strain independent, as they similarly inhibited ZIKV strains from both African and Asian/American lineages. Our results support the broad-spectrum antiviral activity of these ten compounds and suggest their use for the development of antiviral treatment options of ZIKV infection.
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Sinegubova, Ekaterina O., Olga A. Kraevaya, Aleksandrina S. Volobueva, Alexander V. Zhilenkov, Alexander F. Shestakov, Sergey V. Baykov, Pavel A. Troshin, and Vladimir V. Zarubaev. "Water-Soluble Fullerene C60 Derivatives Are Effective Inhibitors of Influenza Virus Replication." Microorganisms 11, no. 3 (March 7, 2023): 681. http://dx.doi.org/10.3390/microorganisms11030681.
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The influenza virus genome features a very high mutation rate leading to the rapid selection of drug-resistant strains. Due to the emergence of drug-resistant strains, there is a need for the further development of new potent antivirals against influenza with a broad activity spectrum. Thus, the search for a novel, effective broad-spectrum antiviral agent is a top priority of medical science and healthcare systems. In this paper, derivatives based on fullerenes with broad virus inhibiting activities in vitro against a panel of influenza viruses were described. The antiviral properties of water-soluble fullerene derivatives were studied. It was demonstrated that the library of compounds based on fullerenes has cytoprotective activity. Maximum virus-inhibiting activity and minimum toxicity were found with compound 2, containing residues of salts of 2-amino-3-cyclopropylpropanoic acid (CC50 > 300 µg/mL, IC50 = 4.73 µg/mL, SI = 64). This study represents the initial stage in a study of fullerenes as anti-influenza drugs. The results of the study lead us conclude that five leading compounds (1–5) have pharmacological prospects.
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Mounce, Bryan C., Teresa Cesaro, Gonzalo Moratorio, Peter Jan Hooikaas, Anna Yakovleva, Scott W. Werneke, Everett Clinton Smith, et al. "Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses." Journal of Virology 90, no. 21 (August 17, 2016): 9683–92. http://dx.doi.org/10.1128/jvi.01347-16.
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ABSTRACT RNA viruses present an extraordinary threat to human health, given their sudden and unpredictable appearance, the potential for rapid spread among the human population, and their ability to evolve resistance to antiviral therapies. The recent emergence of chikungunya virus, Zika virus, and Ebola virus highlights the struggles to contain outbreaks. A significant hurdle is the availability of antivirals to treat the infected or protect at-risk populations. While several compounds show promise in vitro and in vivo , these outbreaks underscore the need to accelerate drug discovery. The replication of several viruses has been described to rely on host polyamines, small and abundant positively charged molecules found in the cell. Here, we describe the antiviral effects of two molecules that alter polyamine levels: difluoromethylornithine (DFMO; also called eflornithine), which is a suicide inhibitor of ornithine decarboxylase 1 (ODC1), and diethylnorspermine (DENSpm), an activator of spermidine/spermine N 1 -acetyltransferase (SAT1). We show that reducing polyamine levels has a negative effect on diverse RNA viruses, including several viruses involved in recent outbreaks, in vitro and in vivo . These findings highlight the importance of the polyamine biosynthetic pathway to viral replication, as well as its potential as a target in the development of further antivirals or currently available molecules, such as DFMO. IMPORTANCE RNA viruses present a significant hazard to human health, and combatting these viruses requires the exploration of new avenues for targeting viral replication. Polyamines, small positively charged molecules within the cell, have been demonstrated to facilitate infection for a few different viruses. Our study demonstrates that diverse RNA viruses rely on the polyamine pathway for replication and highlights polyamine biosynthesis as a promising drug target.
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SANTORO, M., A. CIUCCI, P. GIANFERRETTI, G. BELARDO, S. LAFRAZIA, S. CARTA, and J. ROSSIGNOL. "Thiazolides: A New Class of Broad-Spectrum Antiviral Drugs Targeting Virus Maturation." Antiviral Research 74, no. 3 (June 2007): A31. http://dx.doi.org/10.1016/j.antiviral.2007.01.019.
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Pelz, Lars, Elena Piagnani, Patrick Marsall, Nancy Wynserski, Marc Dominique Hein, Pavel Marichal-Gallardo, Sascha Young Kupke, and Udo Reichl. "Broad-Spectrum Antiviral Activity of Influenza A Defective Interfering Particles against Respiratory Syncytial, Yellow Fever, and Zika Virus Replication In Vitro." Viruses 15, no. 9 (September 4, 2023): 1872. http://dx.doi.org/10.3390/v15091872.
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New broadly acting and readily available antiviral agents are needed to combat existing and emerging viruses. Defective interfering particles (DIPs) of influenza A virus (IAV) are regarded as promising options for the prevention and treatment of IAV infections. Interestingly, IAV DIPs also inhibit unrelated viral infections by stimulating antiviral innate immunity. Here, we tested the ability of IAV DIPs to suppress respiratory syncytial, yellow fever and Zika virus infections in vitro. In human lung (A549) cells, IAV DIP co-infection inhibited the replication and spread of all three viruses. In contrast, we observed no antiviral activity in Vero cells, which are deficient in the production of interferon (IFN), demonstrating its importance for the antiviral effect. Further, in A549 cells, we observed an enhanced type-I and type-III IFN response upon co-infection that appears to explain the antiviral potential of IAV DIPs. Finally, a lack of antiviral activity in the presence of the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib was detected. This revealed a dependency of the antiviral activity on the JAK/signal transducers and activators of transcription (STAT) signaling pathway. Overall, this study supports the notion that IAV DIPs may be used as broad-spectrum antivirals to treat infections with a variety of IFN-sensitive viruses, particularly respiratory viruses.
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Calistri, Arianna, Anna Luganini, Barbara Mognetti, Elizabeth Elder, Giulia Sibille, Valeria Conciatori, Claudia Del Vecchio, et al. "The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and Other Human Coronaviruses." Microorganisms 9, no. 8 (August 14, 2021): 1731. http://dx.doi.org/10.3390/microorganisms9081731.
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Although coronaviruses (CoVs) have long been predicted to cause zoonotic diseases and pandemics with high probability, the lack of effective anti-pan-CoVs drugs rapidly usable against the emerging SARS-CoV-2 actually prevented a promptly therapeutic intervention for COVID-19. Development of host-targeting antivirals could be an alternative strategy for the control of emerging CoVs infections, as they could be quickly repositioned from one pandemic event to another. To contribute to these pandemic preparedness efforts, here we report on the broad-spectrum CoVs antiviral activity of MEDS433, a new inhibitor of the human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 inhibited the in vitro replication of hCoV-OC43 and hCoV-229E, as well as of SARS-CoV-2, at low nanomolar range. Notably, the anti-SARS-CoV-2 activity of MEDS433 against SARS-CoV-2 was also observed in kidney organoids generated from human embryonic stem cells. Then, the antiviral activity of MEDS433 was reversed by the addition of exogenous uridine or the product of hDHODH, the orotate, thus confirming hDHODH as the specific target of MEDS433 in hCoVs-infected cells. Taken together, these findings suggest MEDS433 as a potential candidate to develop novel drugs for COVID-19, as well as broad-spectrum antiviral agents exploitable for future CoVs threats.
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Boghdeh, Niloufar A., Brittany McGraw, Michael D. Barrera, Carol Anderson, Haseebullah Baha, Kenneth H. Risner, Ifedayo V. Ogungbe, Farhang Alem, and Aarthi Narayanan. "Inhibitors of the Ubiquitin-Mediated Signaling Pathway Exhibit Broad-Spectrum Antiviral Activities against New World Alphaviruses." Viruses 15, no. 3 (February 28, 2023): 655. http://dx.doi.org/10.3390/v15030655.
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New World alphaviruses including Venezuelan Equine Encephalitis Virus (VEEV) and Eastern Equine Encephalitis Virus (EEEV) are mosquito-transmitted viruses that cause disease in humans and equines. There are currently no FDA-approved therapeutics or vaccines to treat or prevent exposure-associated encephalitic disease. The ubiquitin proteasome system (UPS)-associated signaling events are known to play an important role in the establishment of a productive infection for several acutely infectious viruses. The critical engagement of the UPS-associated signaling mechanisms by many viruses as host–pathogen interaction hubs led us to hypothesize that small molecule inhibitors that interfere with these signaling pathways will exert broad-spectrum inhibitory activity against alphaviruses. We queried eight inhibitors of the UPS signaling pathway for antiviral outcomes against VEEV. Three of the tested inhibitors, namely NSC697923 (NSC), bardoxolone methyl (BARM) and omaveloxolone (OMA) demonstrated broad-spectrum antiviral activity against VEEV and EEEV. Dose dependency and time of addition studies suggest that BARM and OMA exhibit intracellular and post-entry viral inhibition. Cumulatively, our studies indicate that inhibitors of the UPS-associated signaling pathways exert broad-spectrum antiviral outcomes in the context of VEEV and EEEV infection, supporting their translational application as therapeutic candidates to treat alphavirus infections.
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De Moraes Gomes, Paulo André Teixeira, Lindomar J. Pena, and Ana C. Lima Leite. "Isatin Derivatives and Their Antiviral Properties Against Arboviruses: A Review." Mini-Reviews in Medicinal Chemistry 19, no. 1 (December 6, 2018): 56–62. http://dx.doi.org/10.2174/1389557518666180424093305.
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Arboviruses have been spreading rapidly throughout the Western Hemisphere in recent decades. Among the arboviruses with high morbidity and mortality are the members of the Alphavirus and Flavivirus genera. Within the first genus, Chikungunya Virus (CHIKV) is considered one of the most challenging human arboviral infection worldwide, against which there is no specific antivirals. Flaviviruses are some of the main viruses responsible for encephalitis, haemorrhagic disease and developmental defects. Dengue virus (DENV), Japanese Encephalitis Virus (JEV), West Nile Virus (WNV) and Zika Virus (ZIKV) are examples of flaviviruses without clinically approved antiviral agents. Thus, the search for new antivirals becomes highly important. One of the strategies that can be employed to obtain new drugs is the identification and utilization of privileged structures. Isatin is an example of a privileged molecular framework, displaying a broad spectrum of biological activities, including antiviral action. Obtaining and studying the antiviral properties of isatin derivatives have helped to identify important agents with potential activity against different arboviruses. This article reviews some of these isatin derivatives, their structures and antiviral properties reported against this important group of viruses.
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Kim, Jin-Hyo, Ricardo Resende, Tom Wennekes, Hong-Ming Chen, Nicole Bance, Sabrina Buchini, Andrew G. Watts, et al. "Mechanism-Based Covalent Neuraminidase Inhibitors with Broad-Spectrum Influenza Antiviral Activity." Science 340, no. 6128 (February 21, 2013): 71–75. http://dx.doi.org/10.1126/science.1232552.
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Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates.
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Sepúlveda, Claudia Soledad, Cybele Carina García, and Elsa Beatriz Damonte. "Inhibitors of Nucleotide Biosynthesis as Candidates for a Wide Spectrum of Antiviral Chemotherapy." Microorganisms 10, no. 8 (August 12, 2022): 1631. http://dx.doi.org/10.3390/microorganisms10081631.
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Emerging and re-emerging viruses have been a challenge in public health in recent decades. Host-targeted antivirals (HTA) directed at cellular molecules or pathways involved in virus multiplication represent an interesting strategy to combat viruses presently lacking effective chemotherapy. HTA could provide a wide range of agents with inhibitory activity against current and future viruses that share similar host requirements and reduce the possible selection of antiviral-resistant variants. Nucleotide metabolism is one of the more exploited host metabolic pathways as a potential antiviral target for several human viruses. This review focuses on the antiviral properties of the inhibitors of pyrimidine and purine nucleotide biosynthesis, with an emphasis on the rate-limiting enzymes dihydroorotate dehydrogenase (DHODH) and inosine monophosphate dehydrogenase (IMPDH) for which there are old and new drugs active against a broad spectrum of pathogenic viruses.
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Zheng, Yucheng, Shiliang Li, Kun Song, Jiajie Ye, Wenkang Li, Yifan Zhong, Ziyan Feng, Simeng Liang, Zeng Cai, and Ke Xu. "A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses." Viruses 14, no. 5 (April 28, 2022): 928. http://dx.doi.org/10.3390/v14050928.
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New strategies to rapidly develop broad-spectrum antiviral therapies are urgently required for emerging and re-emerging viruses. Host-targeting antivirals (HTAs) that target the universal host factors necessary for viral replication are the most promising approach, with broad-spectrum, foresighted function, and low resistance. We and others recently identified that host dihydroorotate dehydrogenase (DHODH) is one of the universal host factors essential for the replication of many acute-infectious viruses. DHODH is a rate-limiting enzyme catalyzing the fourth step in de novo pyrimidine synthesis. Therefore, it has also been developed as a therapeutic target for many diseases relying on cellular pyrimidine resources, such as cancers, autoimmune diseases, and viral or bacterial infections. Significantly, the successful use of DHODH inhibitors (DHODHi) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection further supports the application prospects. This review focuses on the advantages of HTAs and the antiviral effects of DHODHi with clinical applications. The multiple functions of DHODHi in inhibiting viral replication, stimulating ISGs expression, and suppressing cytokine storms make DHODHi a potent strategy against viral infection.
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Komarasamy, Thamil Vaani, Nur Amelia Azreen Adnan, William James, and Vinod RMT Balasubramaniam. "Finding a chink in the armor: Update, limitations, and challenges toward successful antivirals against flaviviruses." PLOS Neglected Tropical Diseases 16, no. 4 (April 28, 2022): e0010291. http://dx.doi.org/10.1371/journal.pntd.0010291.
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Flaviviruses have caused large epidemics and ongoing outbreaks for centuries. They are now distributed in every continent infecting up to millions of people annually and may emerge to cause future epidemics. Some of the viruses from this group cause severe illnesses ranging from hemorrhagic to neurological manifestations. Despite decades of research, there are currently no approved antiviral drugs against flaviviruses, urging for new strategies and antiviral targets. In recent years, integrated omics data-based drug repurposing paired with novel drug validation methodologies and appropriate animal models has substantially aided in the discovery of new antiviral medicines. Here, we aim to review the latest progress in the development of both new and repurposed (i) direct-acting antivirals; (ii) host-targeting antivirals; and (iii) multitarget antivirals against flaviviruses, which have been evaluated both in vitro and in vivo, with an emphasis on their targets and mechanisms. The search yielded 37 compounds that have been evaluated for their efficacy against flaviviruses in animal models; 20 of them are repurposed drugs, and the majority of them exhibit broad-spectrum antiviral activity. The review also highlighted the major limitations and challenges faced in the current in vitro and in vivo evaluations that hamper the development of successful antiviral drugs for flaviviruses. We provided an analysis of what can be learned from some of the approved antiviral drugs as well as drugs that failed clinical trials. Potent in vitro and in vivo antiviral efficacy alone does not warrant successful antiviral drugs; current gaps in studies need to be addressed to improve efficacy and safety in clinical trials.
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Cutrı̀, C. C. C., A. Garozzo, M. A. Siracusa, A. Castro, G. Tempera, M. C. Sarvà, and F. Guerrera. "Synthesis of new 3-methylthio-5-aryl-4-isothiazolecarbonitriles with broad antiviral spectrum." Antiviral Research 55, no. 2 (August 2002): 357–68. http://dx.doi.org/10.1016/s0166-3542(02)00072-4.
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Zemlicka, J., and Y. L. Qiu. "2-Hydroxymethylcyclopropylidenemethylpurines and -pyrimidines - New nucleoside analogs with a broad spectrum antiviral activity." Antiviral Research 34, no. 2 (April 1997): A46. http://dx.doi.org/10.1016/s0166-3542(97)83157-9.
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Paulis, A., A. Onali, P. O. Vidalain, V. Lotteau, C. Jaquemin, A. Corona, S. Distinto, G. L. Delogu, and E. Tramontano. "Identification of new benzofuran derivatives as STING agonists with broad-spectrum antiviral activity." Virus Research 347 (September 2024): 199432. http://dx.doi.org/10.1016/j.virusres.2024.199432.
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Li, Jiao, Yujia Wang, Xiaomeng Hao, Shasha Li, Jia Jia, Yan Guan, Zonggen Peng, et al. "Broad-Spectrum Antiviral Natural Products from the Marine-Derived Penicillium sp. IMB17-046." Molecules 24, no. 15 (August 2, 2019): 2821. http://dx.doi.org/10.3390/molecules24152821.
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A new pyrazine derivative, trypilepyrazinol (1), a new α-pyrone polyketide, (+)-neocitreoviridin (2), and a new ergostane analogue, 3β-hydroxyergosta-8,14,24(28)-trien-7-one (3), were isolated and characterized along with five known compounds from the marine-derived fungus Penicillium sp. IMB17-046. The structures of these new compounds were determined using spectroscopic data analyses (HRESIMS, 1D- and 2D-NMR), X-ray crystallography analysis, and TDDFT ECD calculation. Compounds 1 and 3 exhibited broad-spectrum antiviral activities against different types of viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza A virus (IAV), with IC50 values ranging from 0.5 to 7.7 μM. Compounds 1 and 2 showed antibacterial activities against Helicobacter pylori, a causative pathogen of various gastric diseases, with minimum inhibitory concentration (MIC) values of 1–16 μg/mL.
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Razgulyaeva, D. N., A. M. Klabukov, A. V. Galochkina, A. V. Garshinina, O. N. Zhuravskaya, I. I. Gavrilova, V. A. Manakhov, N. A. Nesterova, A. A. Shtro, and E. F. Panarin. "Evaluation of the Antiviral Activity of Drugs from the Group of Polymer Electrolyte Derivatives against a Wide Range of Viruses." Antibiotics and Chemotherapy 68, no. 9-10 (January 15, 2024): 34–41. http://dx.doi.org/10.37489/0235-2990-2023-68-9-10-34-41.
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Background. The modern healthcare system is constantly improving and introducing new measures to protect the population from viral diseases, but the experience of the COVID-19 pandemic has shown that infections cannot always be controlled on global scale. In this regard, the development of new broad-spectrum antiviral drugs is more relevant than ever.The aim of the study was to investigate the antiviral activity and cytotoxicity of copolymers of sodium styrene sulfonate and vinyl monomers of various chemical structures, as well as to identify promising polymers for the development of new antiviral agents.Materials and methods. 14 copolymers of sodium styrene sulfonate (NaSS) with various functional comonomers were synthesized. Three viruses with different reproduction strategies and transmission methods — respiratory syncytial virus, influenza virus, and herpes virus — were selected for the assessment of antiviral activity.Results. The screening identified copolymers that showed high activity against all three viruses. It was found that the introduction of various functional groups into the structure of NaSS did not decrease antiviral activity, but significantly reduced cytotoxicity. The molecular weight has also shown a noticeable effect on the activity. Different sensitivity of viruses and cells to the studied polymers was revealed, likely due to the structural features of the virus shell and cell wall.Conclusions. The results demonstrate the potential of sodium styrene sulfonate copolymers as a model for developing a broad-spectrum antiviral drug.
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Dell’Annunziata, Federica, Maria Vittoria Morone, Marco Gioia, Ferdinando Cione, Massimiliano Galdiero, Nicola Rosa, Gianluigi Franci, Maddalena De Bernardo, and Veronica Folliero. "Broad-Spectrum Antimicrobial Activity of Oftasecur and Visuprime Ophthalmic Solutions." Microorganisms 11, no. 2 (February 17, 2023): 503. http://dx.doi.org/10.3390/microorganisms11020503.
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Due to the wide etiology of conjunctivitis, the expensive and time-consuming diagnosis requires new therapeutic strategies with broad-spectrum antimicrobial activity and nonselective mechanisms of action. In this context, eye drops could provide an alternative to conventional antimicrobial therapies. Here, we compare the antibacterial and antiviral activity of Oftasecur and Visuprime, commercially available ophthalmic solutions. Cytotoxicity assay was performed on Vero CCL-81 cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) test. Antibacterial efficacy was evaluated on Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae by disk diffusion, broth microdilution methods, and time-killing tests. Furthermore, the antiviral activity against HSV-1 was estimated by co-treatment, cell and viral pretreatment and post-treatment, via plaque reduction assay, fluorescence assessment (GFP-engineered HSV-1), and real-time PCR. After 24 h of exposure, Oftasecur and Visuprime showed a volume-inducing 50% of cytotoxicity of 125 and 15.8 μL, respectively Oftasecur and Visuprime induced 90% antibacterial activity in response to mean volume of 10.0 and 4.4 µL for Gram-positive and Gram-negative strains, respectively. Oftasecur exerted bactericidal action on both bacterial populations, while Visuprime was bacteriostatic on Gram-negative strains and slightly bactericidal on Gram-positive bacteria. A major impact on infectivity occurred by exposure of viral particles to the ophthalmic solutions. In detail, 50% of inhibition was verified by exposing the viral particles to 3.12 and 0.84 μL of Oftasecur and Visuprime, respectively, for 1 h. The reduction of the fluorescence and the expression of the viral genes confirmed the recorded antiviral activity. Due to their high antimicrobial efficiency, Oftasecur and Visuprime could represent a valid empirical strategy for the treatment of conjunctivitis.
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Chou, Yi-ying, Christian Cuevas, Margot Carocci, Sarah H. Stubbs, Minghe Ma, David K. Cureton, Luke Chao, et al. "Identification and Characterization of a Novel Broad-Spectrum Virus Entry Inhibitor." Journal of Virology 90, no. 9 (February 24, 2016): 4494–510. http://dx.doi.org/10.1128/jvi.00103-16.
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ABSTRACTVirus entry into cells is a multistep process that often requires the subversion of subcellular machineries. A more complete understanding of these steps is necessary to develop new antiviral strategies. While studying the potential role of the actin network and one of its master regulators, the small GTPase Cdc42, during Junin virus (JUNV) entry, we serendipitously uncovered the small molecule ZCL278, reported to inhibit Cdc42 function as an entry inhibitor for JUNV and for vesicular stomatitis virus, lymphocytic choriomeningitis virus, and dengue virus but not for the nonenveloped poliovirus. Although ZCL278 did not interfere with JUNV attachment to the cell surface or virus particle internalization into host cells, it prevented the release of JUNV ribonucleoprotein cores into the cytosol and decreased pH-mediated viral fusion with host membranes. We also identified SVG-A astroglial cell-derived cells to be highly permissive for JUNV infection and generated new cell lines expressing fluorescently tagged Rab5c or Rab7a or lacking Cdc42 using clustered regularly interspaced short palindromic repeat (CRISPR)-caspase 9 (Cas9) gene-editing strategies. Aided by these tools, we uncovered that perturbations in the actin cytoskeleton or Cdc42 activity minimally affect JUNV entry, suggesting that the inhibitory effect of ZCL278 is not mediated by ZCL278 interfering with the activity of Cdc42. Instead, ZCL278 appears to redistribute viral particles from endosomal to lysosomal compartments. ZCL278 also inhibited JUNV replication in a mouse model, and no toxicity was detected. Together, our data suggest the unexpected antiviral activity of ZCL278 and highlight its potential for use in the development of valuable new tools to study the intracellular trafficking of pathogens.IMPORTANCEThe Junin virus is responsible for outbreaks of Argentine hemorrhagic fever in South America, where 5 million people are at risk. Limited options are currently available to treat infections by Junin virus or other viruses of theArenaviridae, making the identification of additional tools, including small-molecule inhibitors, of great importance. How Junin virus enters cells is not yet fully understood. Here we describe new cell culture models in which the cells are susceptible to Junin virus infection and to which we applied CRISPR-Cas9 genome engineering strategies to help characterize early steps during virus entry. We also uncovered ZCL278 to be a new antiviral small molecule that potently inhibits the cellular entry of the Junin virus and other enveloped viruses. Moreover, we show that ZCL278 also functionsin vivo, thereby preventing Junin virus replication in a mouse model, opening the possibility for the discovery of ZCL278 derivatives of therapeutic potential.
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Li, Shitao, Lingyan Wang, Bishi Fu, and Martin E. Dorf. "ZMPSTE24 is a novel intrinsic immune protein that restricts a broad-spectrum of viruses." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 217.9. http://dx.doi.org/10.4049/jimmunol.196.supp.217.9.
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Abstract Virus entry begins with attachment to cell-surface receptors and ends with delivery of the viral genome into the cytoplasm. Many enveloped viruses are ferried deep into the cytoplasm through endocytic vesicles and utilize the low pH endosomal environment to activate the fusion process between viral and cellular membranes. Higher vertebrates evolved interferon-induced transmembrane proteins (IFITM) to impede endocytic penetration by a broad spectrum of RNA viruses. However, the molecular mechanism by which IFITM proteins hinder viral entry is not well elucidated. To address the antiviral mechanism of IFITM, we hypothesize that type I interferon (IFN) induces recruitment of co-factors to the IFITM3 protein complex. Proteomic analysis of IFITM3-FLAG protein complex in HEK293 cells revealed that IFN induced IFITM3 to recruit ZMPSTE24, the 7-pass transmembrane zinc metalloprotease whose function in cytoplasmic organelles is not defined. Contrary to IFITM, ZMPSTE24 mRNA and protein expression are not regulated by IFN. But consistent with IFITM, ZMPSTE24 restricts both RNA and DNA viruses using endocytic entry, including influenza A, vesicular stomatitis, sindbis, Ebola, cowpox and vaccinia viruses. Antiviral activity requires ZMPSTE24 endosomal localization and is independent of its protease activity. Furthermore, ZMPSTE24 is recruited to endosomes by IFITM and block viral endocytic entry. These findings identify a new role for ZMPSTE24 as a broad-spectrum intrinsic antiviral protein and the downstream antiviral effector of IFITM.
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Welch, Stephen R., Jessica R. Spengler, Sarah C. Genzer, Payel Chatterjee, Mike Flint, Éric Bergeron, Joel M. Montgomery, Stuart T. Nichol, César G. Albariño, and Christina F. Spiropoulou. "Screening and Identification of Lujo Virus Inhibitors Using a Recombinant Reporter Virus Platform." Viruses 13, no. 7 (June 28, 2021): 1255. http://dx.doi.org/10.3390/v13071255.
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Lujo virus (LUJV), a highly pathogenic arenavirus, was first identified in 2008 in Zambia. To aid the identification of effective therapeutics for LUJV, we developed a recombinant reporter virus system, confirming reporter LUJV comparability with wild-type virus and its utility in high-throughput antiviral screening assays. Using this system, we evaluated compounds with known and unknown efficacy against related arenaviruses, with the aim of identifying LUJV-specific and potential new pan-arenavirus antivirals. We identified six compounds demonstrating robust anti-LUJV activity, including several compounds with previously reported activity against other arenaviruses. These data provide critical evidence for developing broad-spectrum antivirals against high-consequence arenaviruses.
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Andreu, Sabina, Inés Ripa, Raquel Bello-Morales, and José Antonio López-Guerrero. "Valproic Acid and Its Amidic Derivatives as New Antivirals against Alphaherpesviruses." Viruses 12, no. 12 (November 26, 2020): 1356. http://dx.doi.org/10.3390/v12121356.
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Herpes simplex viruses (HSVs) are neurotropic viruses with broad host range whose infections cause considerable health problems in both animals and humans. In fact, 67% of the global population under the age of 50 are infected with HSV-1 and 13% have clinically recurrent HSV-2 infections. The most prescribed antiherpetics are nucleoside analogues such as acyclovir, but the emergence of mutants resistant to these drugs and the lack of available vaccines against human HSVs has led to an imminent need for new antivirals. Valproic acid (VPA) is a branched short-chain fatty acid clinically used as a broad-spectrum antiepileptic drug in the treatment of neurological disorders, which has shown promising antiviral activity against some herpesviruses. Moreover, its amidic derivatives valpromide and valnoctamide also share this antiherpetic activity. This review summarizes the current research on the use of VPA and its amidic derivatives as alternatives to traditional antiherpetics in the fight against HSV infections.
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Ma, Li, and Lei Yao. "Antiviral Effects of Plant-Derived Essential Oils and Their Components: An Updated Review." Molecules 25, no. 11 (June 5, 2020): 2627. http://dx.doi.org/10.3390/molecules25112627.
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The presence of resistance to available antivirals calls for the development of novel therapeutic agents. Plant-derived essential oils may serve as alternative sources of virus-induced disease therapy. Previous studies have demonstrated essential oils to be excellent candidates to treat antiviral-resistant infection associated with their chemical complexity which confers broad-spectrum mechanisms of action and non-specific antiviral properties. However, almost no comprehensive reviews are updated to generalize knowledge in this regard and disclose the interplay between the components and their antiviral activities. This review provides an up-to-date overview of the antiviral efficacy of essential oils from a wide range of plant species and their characteristic components, as well as their overall mechanisms of action, focusing on the last decade. The roles of individual components relative to the overall antiviral efficacy of essential oils, together with the antiviral activity of essential oils in comparison with commercial drugs are also discussed. Lastly, the inadequacies in current research and future research are put forward. This review will provide references in the design of new drug prototypes and improve our understanding of the proper applications of essential oils in the future.
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Luteijn, Rutger D., Patrique Praest, Frank Thiele, Saravanan Manikam Sadasivam, Katrin Singethan, Jan W. Drijfhout, Christian Bach, et al. "A Broad-Spectrum Antiviral Peptide Blocks Infection of Viruses by Binding to Phosphatidylserine in the Viral Envelope." Cells 9, no. 9 (August 29, 2020): 1989. http://dx.doi.org/10.3390/cells9091989.
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The ongoing threat of viral infections and the emergence of antiviral drug resistance warrants a ceaseless search for new antiviral compounds. Broadly-inhibiting compounds that act on elements shared by many viruses are promising antiviral candidates. Here, we identify a peptide derived from the cowpox virus protein CPXV012 as a broad-spectrum antiviral peptide. We found that CPXV012 peptide hampers infection by a multitude of clinically and economically important enveloped viruses, including poxviruses, herpes simplex virus-1, hepatitis B virus, HIV-1, and Rift Valley fever virus. Infections with non-enveloped viruses such as Coxsackie B3 virus and adenovirus are not affected. The results furthermore suggest that viral particles are neutralized by direct interactions with CPXV012 peptide and that this cationic peptide may specifically bind to and disrupt membranes composed of the anionic phospholipid phosphatidylserine, an important component of many viral membranes. The combined results strongly suggest that CPXV012 peptide inhibits virus infections by direct interactions with phosphatidylserine in the viral envelope. These results reiterate the potential of cationic peptides as broadly-acting virus inhibitors.
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Maffei, Massimo E., Cristiano Salata, and Giorgio Gribaudo. "Tackling the Future Pandemics: Broad-Spectrum Antiviral Agents (BSAAs) Based on A-Type Proanthocyanidins." Molecules 27, no. 23 (November 30, 2022): 8353. http://dx.doi.org/10.3390/molecules27238353.
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A-type proanthocyanidins (PAC-As) are plant-derived natural polyphenols that occur as oligomers or polymers of flavan-3-ol monomers, such as (+)-catechin and (−)-epicatechin, connected through an unusual double A linkage. PAC-As are present in leaves, seeds, flowers, bark, and fruits of many plants, and are thought to exert protective natural roles against microbial pathogens, insects, and herbivores. Consequently, when tested in isolation, PAC-As have shown several biological effects, through antioxidant, antibacterial, immunomodulatory, and antiviral activities. PAC-As have been observed in fact to inhibit replication of many different human viruses, and both enveloped and non-enveloped DNA and RNA viruses proved sensible to their inhibitory effect. Mechanistic studies revealed that PAC-As cause reduction of infectivity of viral particles they come in contact with, as a result of their propensity to interact with virion surface capsid proteins or envelope glycoproteins essential for viral attachment and entry. As viral infections and new virus outbreaks are a major public health concern, development of effective Broad-Spectrum Antiviral Agents (BSAAs) that can be rapidly deployable even against future emerging viruses is an urgent priority. This review summarizes the antiviral activities and mechanism of action of PAC-As, and their potential to be deployed as BSAAs against present and future viral infections.
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Chiang, Cindy, Vladimir Beljanski, Kevin Yin, David Olagnier, Fethia Ben Yebdri, Courtney Steel, Marie-Line Goulet, et al. "Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists." Journal of Virology 89, no. 15 (May 27, 2015): 8011–25. http://dx.doi.org/10.1128/jvi.00845-15.
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ABSTRACTThe cytosolic RIG-I (retinoic acid-inducible gene I) receptor plays a pivotal role in the initiation of the immune response against RNA virus infection by recognizing short 5′-triphosphate (5′ppp)-containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5′ppp RIG-I agonists of varieous lengths, structures, and sequences and evaluated the generation of the antiviral and inflammatory responses in human epithelial A549 cells, human innate immune primary cells, and murine models of influenza and chikungunya viral pathogenesis. A 99-nucleotide, uridine-rich hairpin 5′pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5′pppRNA structures, RIG-I aptamers, or poly(I·C). Interestingly, manipulation of the primary RNA sequence alone was sufficient to modulate antiviral activity and inflammatory response, in a manner dependent exclusively on RIG-I and independent of MDA5 and TLR3. Both prophylactic and therapeutic administration of M8 effectively inhibited influenza virus and dengue virus replicationin vitro. Furthermore, multiple strains of influenza virus that were resistant to oseltamivir, an FDA-approved therapeutic treatment for influenza, were highly sensitive to inhibition by M8. Finally, prophylactic M8 treatmentin vivoprolonged survival and reduced lung viral titers of mice challenged with influenza virus, as well as reducing chikungunya virus-associated foot swelling and viral load. Altogether, these results demonstrate that 5′pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human-pathogenic RNA viruses.IMPORTANCEThe development of novel therapeutics to treat human-pathogenic RNA viral infections is an important goal to reduce spread of infection and to improve human health and safety. This study investigated the design of an RNA agonist with enhanced antiviral and inflammatory properties against influenza, dengue, and chikungunya viruses. A novel, sequence-dependent, uridine-rich RIG-I agonist generated a protective antiviral responsein vitroandin vivoand was effective at concentrations 100-fold lower than prototype sequences or other RNA agonists, highlighting the robust activity and potential clinical use of the 5′pppRNA against RNA virus infection. Altogether, the results identify a novel, sequence-specific RIG-I agonist as an attractive therapeutic candidate for the treatment of a broad range of RNA viruses, a pressing issue in which a need for new and more effective options persists.
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Oien, Nancee L., Roger J. Brideau, Todd A. Hopkins, Janet L. Wieber, Mary L. Knechtel, John A. Shelly, Robert A. Anstadt, et al. "Broad-Spectrum Antiherpes Activities of 4-Hydroxyquinoline Carboxamides, a Novel Class of Herpesvirus Polymerase Inhibitors." Antimicrobial Agents and Chemotherapy 46, no. 3 (March 2002): 724–30. http://dx.doi.org/10.1128/aac.46.3.724-730.2002.
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ABSTRACT Through broad screening of the compound library at Pharmacia, a naphthalene carboxamide was identified as a nonnucleoside inhibitor of human cytomegalovirus (HCMV) polymerase. Structure-activity relationship studies demonstrated that a quinoline ring could be substituted for naphthalene, resulting in the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQC) class of antiviral agents with unique biological properties. In vitro assays with the 4-HQCs have demonstrated potent inhibition of HCMV, herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV) polymerases but no inhibition of human α, δ, and γ polymerases. Antiviral cell culture assays have further confirmed that these compounds are active against HCMV, HSV-1, HSV-2, VZV, and many animal herpesviruses. However, these compounds were not active against several nonherpesviruses representing different DNA and RNA virus families. A strong correlation between the viral DNA polymerase and antiviral activity for this class of compounds supports inhibition of the viral polymerase as the mechanism of antiviral activity. Northern blot analysis of immediate-early and late viral transcripts also pointed to a block in the viral life cycle consistent with inhibition of viral DNA replication. In vitro HCMV polymerase assays indicate that the 4-HQCs are competitive inhibitors of nucleoside binding. However, no cross-resistance could be detected with ganciclovir-resistant HCMV or acyclovir-resistant HSV-1 mutants. The unique, broad-spectrum activities of the 4-HQCs may offer new opportunities for treating many of the diseases caused by herpesviruses.
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Besednova, Natalya N., Boris G. Andryukov, Tatyana A. Kuznetsova, Tatyana S. Zaporozhets, Sergey P. Kryzhanovsky, Svetlana P. Ermakova, and Mikhail Yu Shchelkanov. "Antiviral Effects and Mechanisms of Action of Water Extracts and Polysaccharides of Microalgae and Cyanobacteria." Journal of Pharmacy and Nutrition Sciences 12 (December 13, 2022): 54–73. http://dx.doi.org/10.29169/1927-5951.2022.12.05.
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Microalgae (MA) and cyanobacteria (CB) are currently attracting much attention from scientists due to the high biological activity of many secondary metabolites of these aquatic organisms. This review presents up-to-date modern data on the prospects for using polysaccharides (PS) of these marine aquatic organisms as effective and practically safe antiviral agents. These natural biopolymers are polyvalent compounds, which allows them to bind to several complementary biological target receptors. Particular emphasis is placed on the exopolysaccharides (EPS) Spirulina sp. (Arthrospira sp.), Porphyridium sp., Chlorella sp., and Euglena sp., whose antiviral activity makes them promising for the creation of drugs, biologically active food supplements, and products for functional nutrition. The mechanisms of the biological action of PS and the targets of these compounds are presented with a brief description of PS's anti-inflammatory, immunomodulatory and antioxidant actions, which make the most significant contribution to the antiviral effects. The authors hope to draw the attention of researchers to the use of water extracts and polysaccharides of microalgae and cyanobacteria as potential broad-spectrum antiviral agents that can become the basis for new antivirus strategies.
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Hutterer, Corina, Jan Eickhoff, Jens Milbradt, Klaus Korn, Isabel Zeitträger, Hanife Bahsi, Sabrina Wagner, et al. "A Novel CDK7 Inhibitor of the Pyrazolotriazine Class Exerts Broad-Spectrum Antiviral Activity at Nanomolar Concentrations." Antimicrobial Agents and Chemotherapy 59, no. 4 (January 26, 2015): 2062–71. http://dx.doi.org/10.1128/aac.04534-14.
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ABSTRACTProtein kinases represent central and multifunctional regulators of a balanced virus-host interaction. Cyclin-dependent protein kinase 7 (CDK7) plays crucial regulatory roles in cell cycle and transcription, both connected with the replication of many viruses. Previously, we developed a CDK7 inhibitor, LDC4297, that inhibits CDK7in vitroin the nano-picomolar range. Novel data from a kinome-wide evaluation (>330 kinases profiledin vitro) demonstrate a kinase selectivity. Importantly, we provide first evidence for the antiviral potential of the CDK7 inhibitor LDC4297, i.e., in exerting a block of the replication of human cytomegalovirus (HCMV) in primary human fibroblasts at nanomolar concentrations (50% effective concentration, 24.5 ± 1.3 nM). As a unique feature compared to approved antiherpesviral drugs, inhibition occurred already at the immediate-early level of HCMV gene expression. The mode of antiviral action was considered multifaceted since CDK7-regulated cellular factors that are supportive of HCMV replication were substantially affected by the inhibitors. An effect of LDC4297 was identified in the interference with HCMV-driven inactivation of retinoblastoma protein (Rb), a regulatory step generally considered a hallmark of herpesviral replication. In line with this finding, a broad inhibitory activity of the drug could be demonstrated against a selection of human and animal herpesviruses and adenoviruses, whereas other viruses only showed intermediate drug sensitivity. Summarized, the CDK7 inhibitor LDC4297 is a promising candidate for further antiviral drug development, possibly offering new options for a comprehensive approach to antiviral therapy.
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Litterman, Nadia, Christopher Lipinski, and Sean Ekins. "Small molecules with antiviral activity against the Ebola virus." F1000Research 4 (February 9, 2015): 38. http://dx.doi.org/10.12688/f1000research.6120.1.
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The recent outbreak of the Ebola virus in West Africa has highlighted the clear shortage of broad-spectrum antiviral drugs for emerging viruses. There are numerous FDA approved drugs and other small molecules described in the literature that could be further evaluated for their potential as antiviral compounds. These molecules are in addition to the few new antivirals that have been tested in Ebola patients but were not originally developed against the Ebola virus, and may play an important role as we await an effective vaccine. The balance between using FDA approved drugs versus novel antivirals with minimal safety and no efficacy data in humans should be considered. We have evaluated 55 molecules from the perspective of an experienced medicinal chemist as well as using simple molecular properties and have highlighted 16 compounds that have desirable qualities as well as those that may be less desirable. In addition we propose that a collaborative database for sharing such published and novel information on small molecules is needed for the research community studying the Ebola virus.
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Tripp, Ralph A., and David E. Martin. "Screening Drugs for Broad-Spectrum, Host-Directed Antiviral Activity: Lessons from the Development of Probenecid for COVID-19." Viruses 15, no. 11 (November 14, 2023): 2254. http://dx.doi.org/10.3390/v15112254.
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In the early stages of drug discovery, researchers develop assays that are compatible with high throughput screening (HTS) and structure activity relationship (SAR) measurements. These assays are designed to evaluate the effectiveness of new and known molecular entities, typically targeting specific features within the virus. Drugs that inhibit virus replication by inhibiting a host gene or pathway are often missed because the goal is to identify active antiviral agents against known viral targets. Screening efforts should be sufficiently robust to identify all potential targets regardless of the antiviral mechanism to avoid misleading conclusions.
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Jousselin, Clément, Hugo Pliego-Cortés, Alexia Damour, Magali Garcia, Charles Bodet, Daniel Robledo, Nathalie Bourgougnon, and Nicolas Lévêque. "Anti-SARS-CoV-2 Activity of Polysaccharides Extracted from Halymenia floresii and Solieria chordalis (Rhodophyta)." Marine Drugs 21, no. 6 (June 6, 2023): 348. http://dx.doi.org/10.3390/md21060348.
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Even after hundreds of clinical trials, the search for new antivirals to treat COVID-19 is still relevant. Carrageenans are seaweed sulfated polysaccharides displaying antiviral activity against a wide range of respiratory viruses. The objective of this work was to study the antiviral properties of Halymenia floresii and Solieria chordalis carrageenans against SARS-CoV-2. Six polysaccharide fractions obtained from H. floresii and S. chordalis by Enzyme-Assisted Extraction (EAE) or Hot Water Extraction (HWE) were tested. The effect of carrageenan on viral replication was assessed during infection of human airway epithelial cells with a clinical strain of SARS-CoV-2. The addition of carrageenans at different times of the infection helped to determine their mechanism of antiviral action. The four polysaccharide fractions isolated from H. floresii displayed antiviral properties while the S. chordalis fractions did not. EAE-purified fractions caused a stronger reduction in viral RNA concentration. Their antiviral action is likely related to an inhibition of the virus attachment to the cell surface. This study confirms that carrageenans could be used as first-line treatment in the respiratory mucosa to inhibit the infection and transmission of SARS-CoV-2. Low production costs, low cytotoxicity, and a broad spectrum of antiviral properties constitute the main strengths of these natural molecules.
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Chudinov, M. V. "Ribavirin and its analogs: Сan you teach an old dog new tricks?" Fine Chemical Technologies 14, no. 4 (September 15, 2019): 7–23. http://dx.doi.org/10.32362/2410-6593-2019-14-4-7-23.
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The review article focuses on the current state of synthetic and biological studies of ribavirin analogs. Ribavirin is a broad-spectrum nucleoside antiviral drug with a 50-year long history of research and application, but its mechanism of action still remains unclear. This article examines contemporary views on the antiviral and antitumor effects of ribavirin and its analogs and describes the contradictions and gaps that exist in our knowledge. In recent years, new nucleoside analogs of ribavirin have been synthesized. These ribavirin derivatives modified at the heterocyclic base, have the potential to become the antiviral and antitumor agents of the new generation. Thus, this paper presents a systematic review of antiviral activities, antitumor activities and structure–activity relationship (SAR) correlations of 39 ribavirin analogs created in the past 15 years. Biological targets and possible mechanisms of action of these new compounds are also discussed, as well as the prospects and possible directions for further research.
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Song, Yabin, Yongqiang Deng, Huiqiang Wang, Zhuchun Bei, Hongjing Gu, Hui Zhao, Hong Wang, et al. "Naphthoquine: A Potent Broad-Spectrum Anti-Coronavirus Drug In Vitro." Molecules 27, no. 3 (January 21, 2022): 712. http://dx.doi.org/10.3390/molecules27030712.
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COVID-19 has spread around the world and caused serious public health and social problems. Although several vaccines have been authorized for emergency use, new effective antiviral drugs are still needed. Some repurposed drugs including Chloroquine, Hydroxychloroquine and Remdesivir were immediately used to treat COVID-19 after the pandemic. However, the therapeutic effects of these drugs have not been fully demonstrated in clinical studies. In this paper, we found an antimalarial drug, Naphthoquine, showed good broad-spectrum anti-coronavirus activity. Naphthoquineinhibited HCoV-229E, HCoV-OC43 and SARS-CoV-2 replication in vitro, with IC50 = 2.05 ± 1.44 μM, 5.83 ± 0.74 μM, and 2.01 ± 0.38 µM, respectively. Time-of-addition assay was also performed to explore at which stage Naphthoquine functions during SARS-CoV-2 replication. The results suggested that Naphthoquine may influence virus entry and post-entry replication. Considering the safety of Naphthoquine was even better than that of Chloroquine, we think Naphthoquine has the potential to be used as a broad-spectrum drug for coronavirus infection.
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Moskalik, Mikhail Yu. "Sulfonamides with Heterocyclic Periphery as Antiviral Agents." Molecules 28, no. 1 (December 21, 2022): 51. http://dx.doi.org/10.3390/molecules28010051.
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Sulfonamides are the basic motifs for a whole generation of drugs from a large group of antibiotics. Currently, research in the field of the new sulfonamide synthesis has received a “second wind”, due to the increase in the synthetic capabilities of organic chemistry and the study of their medical and biological properties of a wide spectrum of biological activity. New reagents and new reactions make it possible to significantly increase the number of compounds with a sulfonamide fragment in combination with other important pharmacophore groups, such as, for example, a wide class of N-containing heterocycles. The result of these synthetic possibilities is the extension of the activity spectrum—along with antibacterial activity, many of them exhibit other types of biological activity. Antiviral activity is also observed in a wide range of sulfonamide derivatives. This review provides examples of the synthesis of sulfonamide compounds with antiviral properties that can be used to develop drugs against coxsackievirus B, enteroviruses, encephalomyocarditis viruses, adenoviruses, human parainfluenza viruses, Ebola virus, Marburg virus, SARS-CoV-2, HIV and others. Since over the past three years, viral infections have become a special problem for public health throughout the world, the development of new broad-spectrum antiviral drugs is an extremely important task for synthetic organic and medicinal chemistry. Sulfonamides can be both sources of nitrogen for building a nitrogen-containing heterocyclic core and the side chain substituents of a biologically active substance. The formation of the sulfonamide group is often achieved by the reaction of the N-nucleophilic center in the substrate molecule with the corresponding sulfonylchloride. Another approach involves the use of sulfonamides as the reagents for building a nitrogen-containing framework.
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Gao, Yongyue, Xingxing He, Lili Yan, Hongyu Zhang, Sijia Liu, Qian Ma, Peiyao Zhang, et al. "Discovery of Barakacin and Its Derivatives as Novel Antiviral and Fungicidal Agents." Molecules 28, no. 7 (March 29, 2023): 3032. http://dx.doi.org/10.3390/molecules28073032.
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Pesticides are essential for the development of agriculture. It is urgent to develop green, safe and efficient pesticides. Bisindole alkaloids have unique and concise structures and broad biological activities, which make them an important leading skeleton in the creation of new pesticides. In this work, we synthesized bisindole alkaloid barakacin in a simple seven-step process, and simultaneously designed and synthesized a series of its derivatives. Biological activity research indicated that most of these compounds displayed good antiviral activities against tobacco mosaic virus (TMV). Among them, compound 14b exerted a superior inhibitory effect in comparison to commercially available antiviral agent ribavirin, and could be expected to become a novel antiviral candidate. Molecular biology experiments and molecular docking research found that the potential target of compound 14b was TMV coat protein (CP). These compounds also showed broad-spectrum anti-fungal activities against seven kinds of plant fungi.
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Bonotto, Rafaela M., Glaucia Souza-Almeida, Soraya Jabur Badra, Luiz Tadeu Figueiredo, Carolina B. Moraes, and Lucio H. Freitas-Junior. "Evaluation of broad-spectrum antiviral compounds against chikungunya infection using a phenotypic screening strategy." F1000Research 7 (October 31, 2018): 1730. http://dx.doi.org/10.12688/f1000research.16498.1.
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Chikungunya fever is an emerging disease and a significant public health problem in tropical countries. Recently reported outbreaks in Brazil in 2015 drew attention to the need to develop prevention and treatment options, as no antiviral chemotherapy or vaccines are currently available for this disease. Two strategies have been proved to accelerate the discovery of new anti-infectives: phenotypic screening and drug repurposing. Phenotypic screening can support the fast interrogation of compounds without the need for a pre-validated drug target, which is not available for the chikungunya virus (CHIKV) and has the additional advantage of facilitating the discovery of antiviral with novel mechanism of action. Drug repurposing can save time and resources in drug development by enabling secondary uses for drugs that are already approved for human treatment, thus precluding the need for several of the mandatory preclinical and clinical studies necessary for drug approval. A phenotypic screening assay was developed by infecting the human hepatoma Huh-7 cells with CHIKV 181/25 and quantifying infection through indirect immunofluorescence. The compound 6-azauridine was used as a positive control drug. The screening assay was validated by testing a commercial library of 1,280 compounds, including FDA-approved drugs, and used to screen a panel of broad-spectrum antiviral compounds for anti-CHIKV activity. A high content assay was set up in Huh-7 cells-infected with CHIKV. The maximum rate of infection peaked at 48 hours post-infection, after which the host cell number was greatly reduced due to a strong cytopathic effect. Assay robustness was confirmed with Z’-factor values >0.8 and high correlation coefficient between independent runs, demonstrating that the assay is reliable, consistent and reproducible. Among tested compounds, sofosbuvir, an anti-hepatitis C virus drug, exhibited good selectivity against CHIKV with an EC50of 11 µM, suggesting it is a promising candidate for repurposing.
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Covés-Datson, Evelyn M., Steven R. King, Maureen Legendre, Auroni Gupta, Susana M. Chan, Emily Gitlin, Vikram V. Kulkarni, et al. "A molecularly engineered antiviral banana lectin inhibits fusion and is efficacious against influenza virus infection in vivo." Proceedings of the National Academy of Sciences 117, no. 4 (January 13, 2020): 2122–32. http://dx.doi.org/10.1073/pnas.1915152117.
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There is a strong need for a new broad-spectrum antiinfluenza therapeutic, as vaccination and existing treatments are only moderately effective. We previously engineered a lectin, H84T banana lectin (H84T), to retain broad-spectrum activity against multiple influenza strains, including pandemic and avian, while largely eliminating the potentially harmful mitogenicity of the parent compound. The amino acid mutation at position 84 from histidine to threonine minimizes the mitogenicity of the wild-type lectin while maintaining antiinfluenza activity in vitro. We now report that in a lethal mouse model H84T is indeed nonmitogenic, and both early and delayed therapeutic administration of H84T intraperitoneally are highly protective, as is H84T administered subcutaneously. Mechanistically, attachment, which we anticipated to be inhibited by H84T, was only somewhat decreased by the lectin. Instead, H84T is internalized into the late endosomal/lysosomal compartment and inhibits virus–endosome fusion. These studies reveal that H84T is efficacious against influenza virus in vivo, and that the loss of mitogenicity seen previously in tissue culture is also seen in vivo, underscoring the potential utility of H84T as a broad-spectrum antiinfluenza agent.