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1
Frederickson, Robert. "Antiviral protease inhibitors." Nature Biotechnology 17, no. 12 (December 1999): 1150. http://dx.doi.org/10.1038/70677.
Повний текст джерела
2
Wang, Q. May, Robert B. Johnson, Louis N. Jungheim, Jeffrey D. Cohen, and Elcira C. Villarreal. "Dual Inhibition of Human Rhinovirus 2A and 3C Proteases by Homophthalimides." Antimicrobial Agents and Chemotherapy 42, no. 4 (April 1, 1998): 916–20. http://dx.doi.org/10.1128/aac.42.4.916.
Повний текст джерелаАнотація:
ABSTRACT The 2A and 3C proteases encoded by human rhinoviruses (HRVs) are attractive targets for antiviral drug development due to their important roles in viral replication. Homophthalimides were originally identified as inhibitors of rhinovirus 3C protease through our screening effort. Previous studies have indicated that the antiviral activity of certain homophthalimides exceeded their in vitro inhibitory activity against the viral 3C protease, suggesting that an additional mechanism might be involved. Reported here is the identification of homophthalimides as potent inhibitors for another rhinovirus protease, designated 2A. Several homophthalimides exhibit time-dependent inhibition of the 2A protease in the low-micromolar range, and enzyme-inhibitor complexes were identified by mass spectrometry. Compound LY343814, one of the most potent inhibitors against HRV14 2A protease, had an antiviral 50% inhibitory concentration of 4.2 μM in the cell-based assay. Our data reveal that homophthalimides are not only 3C but also 2A protease inhibitors in vitro, implying that the antiviral activity associated with these compounds might result from inactivation of both 2A and 3C proteases in vivo. Since the processing of the viral polyprotein is hierarchical, dual inhibition of the two enzymes may result in cooperative inhibition of viral replication. On the basis of the current understanding of their enzyme inhibitory mechanism, homophthalimides, as a group of novel nonpeptidic antirhinovirus agents, merit further structure-action relationship studies.
3
Mello, Chris, Esmeralda Aguayo, Madeleine Rodriguez, Gary Lee, Robert Jordan, Tomas Cihlar, and Gabriel Birkus. "Multiple Classes of Antiviral Agents ExhibitIn VitroActivity against Human Rhinovirus Type C." Antimicrobial Agents and Chemotherapy 58, no. 3 (December 23, 2013): 1546–55. http://dx.doi.org/10.1128/aac.01746-13.
Повний текст джерелаАнотація:
ABSTRACTHuman rhinovirus type C (HRV-C) is a newly discovered enterovirus species frequently associated with exacerbation of asthma and other acute respiratory conditions. Until recently, HRV-C could not be propagatedin vitro, hampering in-depth characterization of the virus replication cycle and preventing efficient testing of antiviral agents. Herein we describe several subgenomic RNA replicon systems and a cell culture infectious model for HRV-C that can be used for antiviral screening. The replicon constructs consist of genome sequences from HRVc15, HRVc11, HRVc24, and HRVc25 strains, with the P1 capsid region replaced by aRenillaluciferase coding sequence. Following transfection of the replicon RNA into HeLa cells, the constructs produced time-dependent increases in luciferase signal that can be inhibited in a dose-dependent manner by known inhibitors of HRV replication, including the 3C protease inhibitor rupintrivir, the nucleoside analog inhibitor MK-0608, and the phosphatidylinositol 4-kinase IIIβ (PI4K-IIIβ) kinase inhibitor PIK93. Furthermore, with the exception of pleconaril and pirodavir, the other tested classes of HRV inhibitors blocked the replication of full-length HRVc15 and HRVc11 in human airway epithelial cells (HAEs) that were differentiated in the air-liquid interface, exhibiting antiviral activities similar to those observed with HRV-16. In summary, this study is the first comprehensive profiling of multiple classes of antivirals against HRV-C, and the set of newly developed quantitative HRV-C antiviral assays represent indispensable tools for the identification and evaluation of novel panserotype HRV inhibitors.
4
Vinson, Valda. "Promising antiviral protease inhibitors." Science 368, no. 6497 (June 18, 2020): 1324.2–1324. http://dx.doi.org/10.1126/science.368.6497.1324-b.
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5
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.
Повний текст джерелаАнотація:
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.
6
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.
Повний текст джерелаАнотація:
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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De Nicolò, Amedeo, Marco Simiele, Andrea Calcagno, Adnan Mohamed Abdi, Stefano Bonora, Giovanni Di Perri, and Antonio D'Avolio. "Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens." Antimicrobial Agents and Chemotherapy 58, no. 7 (May 5, 2014): 4042–47. http://dx.doi.org/10.1128/aac.00104-14.
Повний текст джерелаАнотація:
ABSTRACTProtease inhibitors are largely used for the treatment of HIV infection in combination with other antiretroviral drugs. Their improved pharmacokinetic profiles can be achieved through the concomitant administration of low doses of ritonavir (RTV), a protease inhibitor currently used as a booster, increasing the exposure of companion drugs. Since ritonavir-boosted regimens are associated with long-term adverse events, cobicistat, a CYP3A4 inhibitor without antiviral activity, has been developed. Recently, high intracellular concentrations of ritonavir in lymphocytes and monocytes were reported even when ritonavir was administered at low doses, so we aimed to compare its theoretical antiviral activity with those of the associated protease inhibitors. Intracellular concentrations of ritonavir and different protease inhibitors were determined through the same method. Inhibitory constants were obtained from the literature. The study enrolled 103 patients receiving different boosted protease inhibitors, darunavir-ritonavir 600 and 100 mg twice daily and 800 and 100 mg once daily (n= 22 and 4, respectively), atazanavir-ritonavir 300 and 100 mg once daily (n= 40), lopinavir-ritonavir 400 and 100 mg twice daily (n= 21), or tipranavir-ritonavir 500 and 200 mg twice daily (n= 16). According to the observed concentrations, we calculated the ratios between the intracellular concentrations of ritonavir and those of the companion protease inhibitor and between the theoretical viral protease reaction speeds with each drug, with and without ritonavir. The median ratios were 4.04 and 0.63 for darunavir-ritonavir twice daily, 2.49 and 0.74 for darunavir-ritonavir once daily, 0.42 and 0.74 for atazanavir-ritonavir, 0.57 and 0.95 for lopinavir-ritonavir, and 0.19 and 0.84 for tipranavir-ritonavir, respectively. Therefore, the antiviral effect of ritonavir was less than that of the concomitant protease inhibitors but, importantly, mostly with darunavir. Thus, furtherin vitroandin vivostudies of the RTV antiviral effect are warranted.
8
Holý, Antonín, Ivan Votruba, and Erik De Clercq. "Structure-activity studies on open-chain analogues of nucleosides: Inhibition of S-adenosyl-L-homocysteine hydrolase and antiviral activity 1. Neutral open-chain analogues." Collection of Czechoslovak Chemical Communications 50, no. 1 (1985): 245–61. http://dx.doi.org/10.1135/cccc19850245.
Повний текст джерелаАнотація:
Over 70 alkyl derivatives of purine bases were examined for their inhibitory effects toward rat liver S-adenosyl-L-homocysteine hydrolase and their antiviral activity. The following structural features must be fulfilled by an inhibitor of SAH-hydrolase: an intact adenine moiety, an alkyl chain bound at the 9-position and bearing a vicinal diol at the 2',3'-position, with 2S configuration. An additional substitution at the 3-position lowers or annihilates the inhibitory activity. The enzyme inhibition is reversible. Some of the compounds are substrates of adenosine aminohydrolase. All inhibitors of SAH-hydrolase exhibit antiviral activity, e.g. against vesicular stomatitis virus and vaccinia virus in cell culture, and this antiviral correlates with the inhibition of SAH-hydrolase.
9
Hewajuli, Dyah Ayu, and NLPI Dharmayanti. "Efficacy, Mechanism and Antiviral Resistance of Neuraminidase Inhibitors and Adamantane against Avian Influenza." Indonesian Bulletin of Animal and Veterinary Sciences 29, no. 2 (December 4, 2019): 61. http://dx.doi.org/10.14334/wartazoa.v29i2.1951.
Повний текст джерелаАнотація:
Vaccination and antiviral drug are often used to control influenza. However, the effectiveness of vaccine was impaired due to the emergence of new variant of virus strain. Antiviral drug consists of prophylactic and curative substances, namely M2 ion channel inhibitors (adamantane; amantadine and rimantadine) and neuraminidase (NA) inhibitors (NAIs; oseltamivir, zanamivir, peramivir, laninamivir). The synthesis and modification of antiviral neuraminidase (NA) inhibitors (NAIs) and adamantanes increased the antiviral effectiveness. The mechanism of the neuraminidase inhibitor is to prevent influenza infection by inhibiting the release of the virus from internal cells. Adamantane is antiviral drug that selectively inhibits the flow of H+ ions through M2 protein to prevent the uncoating virus particles getting into the endosome. The substitution of (H275Y, S247N, I223L, K150N, R292K, I222T, R152K, R118K, E119V) on NA protein caused resistance of avian influenza virus against the neuraminidase inhibitor. The combination of mutations (S247N, I223L, K150N) increased the resistance of influenza A (H5N1) virus. The diffusion of adamantane resistance varies among HA subtypes, the species of host, the period of isolation, and region. Mutations at residues of 26, 27, 30, 31 or 34 transmembrane M2 protein caused adamantane resistance. The unique substitution (V27I) of M2 protein of clade 2.3.2 H5N1 subtype isolated in Indonesia in 2016 has been contributed to the amantadine resistance. Antiviral combination of M2 ion channel inhibitors and neuraminidase (NA) inhibitors is effective treatments for the resistance.
10
Hayden, Frederick G. "Perspectives on antiviral use during pandemic influenza." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1416 (December 29, 2001): 1877–84. http://dx.doi.org/10.1098/rstb.2001.1007.
Повний текст джерелаАнотація:
Antiviral agents could potentially play a major role in the initial response to pandemic influenza, particularly with the likelihood that an effective vaccine is unavailable, by reducing morbidity and mortality. The M2 inhibitors are partially effective for chemoprophylaxis of pandemic influenza and evidence from studies of interpandemic influenza indicate that the neuraminidase inhibitors would be effective in prevention. In addition to the symptom benefit observed with M2 inhibitor treatment, early therapeutic use of neuraminidase inhibitors has been shown to reduce the risk of lower respiratory complications. Clinical pharmacology and adverse drug effect profiles indicate that the neuraminidase inhibitors and rimantadine are preferable to amantadine with regard to the need for individual prescribing and tolerance monitoring. Transmission of drug-resistant virus could substantially limit the effectiveness of M2 inhibitors and the possibility exists for primary M2 inhibitor resistance in a pandemic strain. The frequency of resistance emergence is lower with neuraminidase inhibitors and mathematical modelling studies indicate that the reduced transmissibility of drug-resistant virus observed with neuraminidase inhibitor-resistant variants would lead to negligible community spread of such variants. Thus, there are antiviral drugs currently available that hold considerable promise for response to pandemic influenza before a vaccine is available, although considerable work remains in realizing this potential. Markedly increasing the quantity of available antiviral agents through mechanisms such as stockpiling, educating health care providers and the public and developing effective means of rapid distribution to those in need are essential in developing an effective response, but remain currently unresolved problems.
11
Canal, Berta, Allison W. McClure, Joseph F. Curran, Mary Wu, Rachel Ulferts, Florian Weissmann, Jingkun Zeng, et al. "Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease." Biochemical Journal 478, no. 13 (July 2, 2021): 2445–64. http://dx.doi.org/10.1042/bcj20210198.
Повний текст джерелаАнотація:
SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is an urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonuclease in vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.
12
Koban, Robert, Markus Neumann, Philipp P. Nelson, and Heinz Ellerbrok. "Differential Efficacy of Novel Antiviral Substances in 3D and Monolayer Cell Culture." Viruses 12, no. 11 (November 12, 2020): 1294. http://dx.doi.org/10.3390/v12111294.
Повний текст джерелаАнотація:
Repurposing of approved drugs that target host functions also important for virus replication promises to overcome the shortage of antiviral therapeutics. Mostly, virus biology including initial screening of antivirals is studied in conventional monolayer cells. The biology of these cells differs considerably from infected tissues. 3D culture models with characteristics of human tissues may reflect more realistically the in vivo events during infection. We screened first, second, and third generation epidermal growth factor receptor (EGFR)-inhibitors with different modes of action and the EGFR-blocking monoclonal antibody cetuximab in a 3D cell culture infection model with primary human keratinocytes and cowpox virus (CPXV) for antiviral activity. Antiviral activity of erlotinib and osimertinib was nearly unaffected by the cultivation method similar to the virus-directed antivirals tecovirimat and cidofovir. In contrast, the host-directed inhibitors afatinib and cetuximab were approx. 100-fold more efficient against CPXV in the 3D infection model, similar to previous results with gefitinib. In summary, inhibition of EGFR-signaling downregulates virus replication comparable to established virus-directed antivirals. However, in contrast to virus-directed inhibitors, in vitro efficacy of host-directed antivirals might be seriously affected by cell cultivation. Results obtained for afatinib and cetuximab suggest that screening of such drugs in standard monolayer culture might underestimate their potential as antivirals.
13
Álvarez-Fernández, Hadrián, Patricia Mingo-Casas, Ana-Belén Blázquez, Flavia Caridi, Juan Carlos Saiz, María-Jesús Pérez-Pérez, Miguel A. Martín-Acebes, and Eva-María Priego. "Allosteric Inhibition of Neutral Sphingomyelinase 2 (nSMase2) by DPTIP: From Antiflaviviral Activity to Deciphering Its Binding Site through In Silico Studies and Experimental Validation." International Journal of Molecular Sciences 23, no. 22 (November 11, 2022): 13935. http://dx.doi.org/10.3390/ijms232213935.
Повний текст джерелаАнотація:
Flavivirus comprises globally emerging and re-emerging pathogens such as Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV), among others. Although some vaccines are available, there is an unmet medical need as no effective antiviral treatment has been approved for flaviviral infections. The development of host-directed antivirals (HDAs) targeting host factors that are essential for viral replication cycle offers the opportunity for the development of broad-spectrum antivirals. In the case of flaviviruses, recent studies have revealed that neutral sphingomyelinase 2, (nSMase2), involved in lipid metabolism, plays a key role in WNV and ZIKV infection. As a proof of concept, we have determined the antiviral activity of the non-competitive nSMase2 inhibitor DPTIP against WNV and ZIKV virus. DPTIP showed potent antiviral activity with EC50 values of 0.26 µM and 1.56 µM for WNV and ZIKV, respectively. In order to unravel the allosteric binding site of DPTIP in nSMase2 and the details of the interaction, computational studies have been carried out. These studies have revealed that DPTIP could block the DK switch in nSMase2. Moreover, the analysis of the residues contributing to the binding identified His463 as a crucial residue. Interestingly, the inhibitory activity of DPTIP on the H463A mutant protein supported our hypothesis. Thus, an allosteric cavity in nSMase2 has been identified that can be exploited for the development of new inhibitors with anti-flaviviral activity.
14
Eltahla, Auda A., Kun Lee Lim, John-Sebastian Eden, Andrew G. Kelly, Jason M. Mackenzie, and Peter A. White. "Nonnucleoside Inhibitors of Norovirus RNA Polymerase: Scaffolds for Rational Drug Design." Antimicrobial Agents and Chemotherapy 58, no. 6 (March 17, 2014): 3115–23. http://dx.doi.org/10.1128/aac.02799-13.
Повний текст джерелаАнотація:
ABSTRACTNorovirus (NoV) is the leading cause of acute gastroenteritis worldwide, causing over 200,000 deaths a year. NoV is nonenveloped, with a single-stranded RNA genome, and is primarily transmitted person to person. The viral RNA-dependent RNA polymerase (RdRp) is critical for the production of genomic and subgenomic RNA and is therefore a prime target for antiviral therapies. Using high-throughput screening, nearly 20,000 “lead-like” compounds were tested for inhibitory activity against the NoV genogroup II, genotype 4 (GII.4) RdRp. The four most potent hits demonstrated half-maximal inhibitory concentrations (IC50s) between 5.0 μM and 9.8 μM against the target RdRp. Compounds NIC02 and NIC04 revealed a mixed mode of inhibition, while NIC10 and NIC12 were uncompetitive RdRp inhibitors. When examined using enzymes from related viruses, NIC02 demonstrated broad inhibitory activity while NIC04 was the most specific GII.4 RdRp inhibitor. The antiviral activity was examined using available NoV cell culture models; the GI.1 replicon and the infectious GV.1 murine norovirus (MNV). NIC02 and NIC04 inhibited the replication of the GI.1 replicon, with 50% effective concentrations (EC50s) of 30.1 μM and 71.1 μM, respectively, while NIC10 and NIC12 had no observable effect on the NoV GI.1 replicon. In the MNV model, NIC02 reduced plaque numbers, size, and viral RNA levels in a dose-dependent manner (EC50s between 2.3 μM and 4.8 μM). The remaining three compounds also reduced MNV replication, although with higher EC50s, ranging from 32 μM to 38 μM. In summary, we have identified novel nonnucleoside inhibitor scaffolds that will provide a starting framework for the development and future optimization of targeted antivirals against NoV.
15
Asahchop, Eugene L., Mark A. Wainberg, Richard D. Sloan, and Cécile L. Tremblay. "Antiviral Drug Resistance and the Need for Development of New HIV-1 Reverse Transcriptase Inhibitors." Antimicrobial Agents and Chemotherapy 56, no. 10 (June 25, 2012): 5000–5008. http://dx.doi.org/10.1128/aac.00591-12.
Повний текст джерелаАнотація:
ABSTRACTHighly active antiretroviral therapy (HAART) consists of a combination of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. Despite being the first antivirals described to be effective against HIV, reverse transcriptase inhibitors remain the cornerstone of HAART. There are two broad classes of reverse transcriptase inhibitor, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first such compounds were developed, viral resistance to them has inevitably been described; this necessitates the continuous development of novel compounds within each class. In this review, we consider the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second-line therapy and describe the patterns of resistance associated with their use as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with a low genetic barrier are more commonly used in resource-limited settings. Their use results in the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings.
16
Ma, Ling, Jiajia Wen, Biao Dong, Jinming Zhou, Shangjiu Hu, Juxian Wang, Yucheng Wang, Mei Zhu, and Shan Cen. "Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants." International Journal of Molecular Sciences 23, no. 22 (November 16, 2022): 14178. http://dx.doi.org/10.3390/ijms232214178.
Повний текст джерелаАнотація:
With the increasing prevalence of drug-resistant variants, novel potent HIV-1 protease inhibitors with broad-spectrum antiviral activity against multidrug-resistant causative viruses are urgently needed. Herein, we designed and synthesized a new series of HIV-1 protease inhibitors with phenols or polyphenols as the P2 ligands and a variety of sulfonamide analogs as the P2′ ligands. A number of these new inhibitors showed superb enzymatic inhibitory activity and antiviral activity. In particular, inhibitors 15d and 15f exhibited potent enzymatic inhibitory activity in the low picomolar range, and the latter showed excellent activity against the Darunavir-resistant HIV-1 variant. Furthermore, the molecular modeling studies provided insight into the ligand-binding site interactions between inhibitors and the enzyme cavity, and they sparked inspiration for the further optimization of potent inhibitors.
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Langendries, Lana, Rana Abdelnabi, Johan Neyts, and Leen Delang. "Repurposing Drugs for Mayaro Virus: Identification of EIDD-1931, Favipiravir and Suramin as Mayaro Virus Inhibitors." Microorganisms 9, no. 4 (March 31, 2021): 734. http://dx.doi.org/10.3390/microorganisms9040734.
Повний текст джерелаАнотація:
Despite the emerging threat of the Mayaro virus (MAYV) in Central and South-America, there are no licensed antivirals or vaccines available for this neglected mosquito-borne virus. Here, we optimized a robust antiviral assay based on the inhibition of the cytopathogenic effect that could be used for high-throughput screening to identify MAYV inhibitors. We first evaluated different cell lines and virus inputs to determine the best conditions for a reliable and reproducible antiviral assay. Next, we used this assay to evaluate a panel of antiviral compounds with known activity against other arboviruses. Only three drugs were identified as inhibitors of MAYV: β-D-N4-hydroxycytidine (EIDD-1931), favipiravir and suramin. The in vitro anti-MAYV activity of these antiviral compounds was further confirmed in a virus yield assay. These antivirals can therefore serve as reference compounds for future anti-MAYV compound testing. In addition, it is of interest to further explore the activity of EIDD-1931 and its orally bioavailable pro-drug molnupiravir in animal infection models to determine whether it offers promise for the treatment of MAYV infection.
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Sacco, Michael Dominic, Chunlong Ma, Panagiotis Lagarias, Ang Gao, Julia Alma Townsend, Xiangzhi Meng, Peter Dube, et al. "Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against Mpro and cathepsin L." Science Advances 6, no. 50 (November 6, 2020): eabe0751. http://dx.doi.org/10.1126/sciadv.abe0751.
Повний текст джерелаАнотація:
The main protease (Mpro) of SARS-CoV-2 is a key antiviral drug target. While most Mpro inhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently found that several Mpro inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II and XII, which are also active against human cathepsin L, a host protease that is important for viral entry. In this study, we solved x-ray crystal structures of Mpro in complex with calpain inhibitors II and XII and three analogs of GC-376. The structure of Mpro with calpain inhibitor II confirmed that the S1 pocket can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. The structure of calpain inhibitor XII revealed an unexpected, inverted binding pose. Together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of dual inhibitors as SARS-CoV-2 antivirals.
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Gudima, Georgii, Ilya Kofiadi, Igor Shilovskiy, Dmitry Kudlay, and Musa Khaitov. "Antiviral Therapy of COVID-19." International Journal of Molecular Sciences 24, no. 10 (May 16, 2023): 8867. http://dx.doi.org/10.3390/ijms24108867.
Повний текст джерелаАнотація:
Since the beginning of the COVID-19 pandemic, the scientific community has focused on prophylactic vaccine development. In parallel, the experience of the pharmacotherapy of this disease has increased. Due to the declining protective capacity of vaccines against new strains, as well as increased knowledge about the structure and biology of the pathogen, control of the disease has shifted to the focus of antiviral drug development over the past year. Clinical data on safety and efficacy of antivirals acting at various stages of the virus life cycle has been published. In this review, we summarize mechanisms and clinical efficacy of antiviral therapy of COVID-19 with drugs based on plasma of convalescents, monoclonal antibodies, interferons, fusion inhibitors, nucleoside analogs, and protease inhibitors. The current status of the drugs described is also summarized in relation to the official clinical guidelines for the treatment of COVID-19. In addition, here we describe innovative drugs whose antiviral effect is provided by antisense oligonucleotides targeting the SARS-CoV-2 genome. Analysis of laboratory and clinical data suggests that current antivirals successfully combat broad spectra of emerging strains of SARS-CoV-2 providing reliable defense against COVID-19.
20
Patick, A. K., and K. E. Potts. "Protease Inhibitors as Antiviral Agents." Clinical Microbiology Reviews 11, no. 4 (October 1, 1998): 614–27. http://dx.doi.org/10.1128/cmr.11.4.614.
Повний текст джерелаАнотація:
SUMMARY Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.
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Alymova, I., G. Taylor, and A. Portner. "Neuraminidase Inhibitors as Antiviral Agents." Current Drug Target -Infectious Disorders 5, no. 4 (December 1, 2005): 401–9. http://dx.doi.org/10.2174/156800505774912884.
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Peel, Michael, and Andrew Scribner. "Cyclophilin inhibitors as antiviral agents." Bioorganic & Medicinal Chemistry Letters 23, no. 16 (August 2013): 4485–92. http://dx.doi.org/10.1016/j.bmcl.2013.05.101.
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Lee, Wei-Ping, Keng-Li Lan, Shi-Xian Liao, Yi-Hsiang Huang, Ming-Chih Hou, and Keng-Hsin Lan. "Inhibitory Effects of Amentoflavone and Orobol on Daclatasvir-Induced Resistance-Associated Variants of Hepatitis C Virus." American Journal of Chinese Medicine 46, no. 04 (January 2018): 835–52. http://dx.doi.org/10.1142/s0192415x18500441.
Повний текст джерелаАнотація:
Hepatitis C virus (HCV) is recognized as a major causative agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Despite rapid progress in the development of direct-acting antivirals (DAA) against HCV infection in recent years, cost-effective antiviral drugs with more affordable prices still need to be developed. In this study, we screened a library of natural compounds to identify natural HCV inhibitors. The library of the pure compounds extracted from Chinese herbs deposited in the chemical bank of National Research Institute of Chinese Medicine (NRICM), Taiwan was screened in the cell culture-derived HCV (HCVcc) system. We identified the flavone or flavan-based compounds amentoflavone, 7,4[Formula: see text]-dihydroxyflavanone, and orobol with the inhibition of viral entry, replication, and translation of the HCV life cycle. Amentoflavone and orobol also showed inhibitory effects on resistant-associated variants to the NS5A inhibitor daclatasvir. The results of this study have the potential to benefit patients who are intolerant to the adverse effect of pegylated interferon or who harbor resistant strains refractory to treatment by current direct-acting antiviral agents.
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Milligan, Jennifer C., Theresa U. Zeisner, George Papageorgiou, Dhira Joshi, Christelle Soudy, Rachel Ulferts, Mary Wu, et al. "Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp5 main protease." Biochemical Journal 478, no. 13 (July 2, 2021): 2499–515. http://dx.doi.org/10.1042/bcj20210197.
Повний текст джерелаАнотація:
The coronavirus 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now being made available, very few antiviral drugs have been approved. The main viral protease (nsp5) of SARS-CoV-2 provides an excellent target for antivirals, due to its essential and conserved function in the viral replication cycle. We have expressed, purified and developed assays for nsp5 protease activity. We screened the nsp5 protease against a custom chemical library of over 5000 characterised pharmaceuticals. We identified calpain inhibitor I and three different peptidyl fluoromethylketones (FMK) as inhibitors of nsp5 activity in vitro, with IC50 values in the low micromolar range. By altering the sequence of our peptidomimetic FMK inhibitors to better mimic the substrate sequence of nsp5, we generated an inhibitor with a subnanomolar IC50. Calpain inhibitor I inhibited viral infection in monkey-derived Vero E6 cells, with an EC50 in the low micromolar range. The most potent and commercially available peptidyl-FMK compound inhibited viral growth in Vero E6 cells to some extent, while our custom peptidyl FMK inhibitor offered a marked antiviral improvement.
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McFadden, Karyn, Patricia Fletcher, Fiorella Rossi, Kantharaju, Muddagowda Umashankara, Vanessa Pirrone, Srivats Rajagopal, et al. "Antiviral Breadth and Combination Potential of Peptide Triazole HIV-1 Entry Inhibitors." Antimicrobial Agents and Chemotherapy 56, no. 2 (November 14, 2011): 1073–80. http://dx.doi.org/10.1128/aac.05555-11.
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ABSTRACTThe first stage of human immunodeficiency virus type 1 (HIV-1) infection involves the fusion of viral and host cellular membranes mediated by viral envelope glycoprotein gp120. Inhibitors that specifically target gp120 are gaining increased attention as therapeutics or preventatives to prevent the spread of HIV-1. One promising new group of inhibitors is the peptide triazoles, which bind to gp120 and simultaneously block its interaction with both CD4 and the coreceptor. In this study, we assessed the most potent peptide triazole, HNG-156, for inhibitory breadth, cytotoxicity, and efficacy, both alone and in combination with other antiviral compounds, against HIV-1. HNG-156 inhibited a panel of 16 subtype B and C isolates of HIV-1 in a single-round infection assay. Inhibition of cell infection by replication-competent clinical isolates of HIV-1 was also observed with HNG-156. We found that HNG-156 had a greater than predicted effect when combined with several other entry inhibitors or the reverse transcriptase inhibitor tenofovir. Overall, we find that HNG-156 is noncytotoxic, has a broad inhibition profile, and provides a positive combination with several inhibitors of the HIV-1 life cycle. These results support the pursuit of efficacy and toxicity analyses in more advanced cell and animal models to develop peptide triazole family inhibitors of HIV-1 into antagonists of HIV-1 infection.
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Wulandari, Dwi, and T. Mirawati Sudiro. "PENGEMBANGAN ANTIVIRUS HUMAN PAPILLOMA VIRUS BERBASIS MOLEKUL KECIL." Majalah Kedokteran Andalas 37, no. 1 (May 3, 2015): 58. http://dx.doi.org/10.22338/mka.v37.i1.p58-63.2014.
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AbstrakSekalipun telah ada program skrining deteksi dini infeksi HPV maupun kanker servis sertaadanya dua vaksin yang telah berlisensi, sekarang ini belum ada obat antivirus yang efektif.Prospek pengembangan molekul kecil inhibitor sebagai antivirus HPV sangat menjanjikan.Modulasi interaksi diantara protein-protein virus atau protein virus dengan protein hospesmenjadi strategi dalam upaya pengembangan molekul inhibitor sebagai antiviral HPV. Halini didukung oleh kemajuan pengetahuan mengenai fungsi protein HPV yang terlibat dalamsiklus hidupnya diantaranya yaitu protein E1, E2, E6 dan E7. Beberapa kandidat antivirustelah ditemukan dan masih dalam penelitian lebih lanjut untuk mendapatkan senyawa turunandengan aktivitas yang lebih tinggi diantaranya asam bifenil sulfonasetat (inhibitor ATPase E1).Indandione dan repaglinide (inhibitor interaksi E1-E2) dan senyawa-senyawa lainnya.AbstractEventhough there has been screening programs for HPV infection and cervical canceras well as the two vaccines that have been licensed, currently there is no effective cure forHPV. The prospects of the development of small molecule inhibitors as HPV antiviral is verypromising. Development strategy was based on the modulation of interactions between viralproteins or viral proteins with host proteins. This is supported by the advances in knowledgeabout HPV’s protein functions involved in their life cycle such as E1, E2, E6 and E7 proteins.Some antiviral molecule candidates have been found and need further studies to obtainderivatives with higher activity including acid biphenyl sulfonasetat (inhibitor ATPase E1),Indandione & repaglinide (inhibitor interaction E1-E2), etc.
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Ishii, H., M. Hasobe, J. G. McKee, D. B. Ault-Riché, and R. T. Borchardt. "Synergistic Antiviral Activity of Inhibitors of S-Adenosylhomocysteine Hydrolase and Ribavirin." Antiviral Chemistry and Chemotherapy 4, no. 2 (April 1993): 127–30. http://dx.doi.org/10.1177/095632029300400207.
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(1′R,2′S,3′R)-9-(2′,3′-Dihydroxycycloperrt-4′-en-1′-yl)-adenine (DHCeA) and -3-deazaadenine (3-deaza-DHCeA), which are potent inhibitors of S-adenosylho-mocysteine (AdoHcy) hydrolase, and ribavirin, which is an inhibitor of IMP-dehydrogenase, were found in this study to have synergistic effects on inhibiting vaccinia virus replication in murine L929 cells without creating a synergistic effect on cellular toxicity. Thus, the antiviral effectiveness of this drug combination was 5–10× higher than the antiviral effectiveness observed with the AdoHcy hydrolase inhibitors alone. Ribavirin does not alter the ability of DHCeA and 3-deaza-DHCeA to elevate the intracellular AdoHcy/S-adeno-sylmethionine (AdoMet) ratio. Increases in this ratio were shown earlier to correlate with the antiviral effects of these carbocyclic nucleosides. Ribavirin was also shown to significantly reduce the cellular level of GTP, which is consistent with its activity as an inhibitor of IMP-dehydrogenase and its proposed mechanism of antiviral action, inhibiting the formation of the ‘capped methylated structure’ at the 5′-end of viral mRNA.
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Tremblay, Cécile L., Françoise Giguel, Christopher Kollmann, Yongbiao Guan, Ting-Chao Chou, Bahige M. Baroudy, and Martin S. Hirsch. "Anti-Human Immunodeficiency Virus Interactions of SCH-C (SCH 351125), a CCR5 Antagonist, with Other Antiretroviral Agents In Vitro." Antimicrobial Agents and Chemotherapy 46, no. 5 (May 2002): 1336–39. http://dx.doi.org/10.1128/aac.46.5.1336-1339.2002.
Повний текст джерелаАнотація:
ABSTRACT SCH-C (SCH 351125) is a small-molecule antagonist of the human immunodeficiency virus type 1(HIV-1) coreceptor CCR5. It has in vitro activity against R5 viruses with 50% inhibitory concentrations ranging from 1.0 to 30.9 nM. We have studied anti-HIV-1 interactions of SCH-C with other antiretroviral agents in vitro. Synergistic interactions were seen with nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine), nonnucleoside reverse transcriptase inhibitors (efavirenz), and protease inhibitors (indinavir) at all inhibitory concentrations evaluated. We have also studied antiviral interactions between the HIV-1 fusion inhibitor T-20 and SCH-C against a panel of R5 HIV-1 isolates. We found synergistic interactions against all the viruses tested, some of which harbored resistance mutations to reverse transcriptase and protease inhibitors. Anti-HIV-1 synergy was also observed between SCH-C and another R5 virus inhibitor, aminooxypentane-RANTES. These findings suggest that SCH-C may be a useful anti-HIV drug in combination regimens and that a combination of chemokine coreceptor/fusion inhibitors may be useful in the treatment of multidrug-resistant viruses.
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Ganter, Benedikt, Martin Zickler, Johanna Huchting, Matthias Winkler, Anna Lüttjohann, Chris Meier, Gülsah Gabriel, and Sebastian Beck. "T-705-Derived Prodrugs Show High Antiviral Efficacies against a Broad Range of Influenza A Viruses with Synergistic Effects When Combined with Oseltamivir." Pharmaceutics 15, no. 6 (June 14, 2023): 1732. http://dx.doi.org/10.3390/pharmaceutics15061732.
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Emerging influenza A viruses (IAV) bear the potential to cause pandemics with unpredictable consequences for global human health. In particular, the WHO has declared avian H5 and H7 subtypes as high-risk candidates, and continuous surveillance of these viruses as well as the development of novel, broadly acting antivirals, are key for pandemic preparedness. In this study, we sought to design T-705 (Favipiravir) related inhibitors that target the RNA-dependent RNA polymerase and evaluate their antiviral efficacies against a broad range of IAVs. Therefore, we synthesized a library of derivatives of T-705 ribonucleoside analogues (called T-1106 pronucleotides) and tested their ability to inhibit both seasonal and highly pathogenic avian influenza viruses in vitro. We further showed that diphosphate (DP) prodrugs of T-1106 are potent inhibitors of H1N1, H3N2, H5N1, and H7N9 IAV replication. Importantly, in comparison to T-705, these DP derivatives achieved 5- to 10-fold higher antiviral activity and were non-cytotoxic at the therapeutically active concentrations. Moreover, our lead DP prodrug candidate showed drug synergy with the neuraminidase inhibitor oseltamivir, thus opening up another avenue for combinational antiviral therapy against IAV infections. Our findings may serve as a basis for further pre-clinical development of T-1106 prodrugs as an effective countermeasure against emerging IAVs with pandemic potential.
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Mathy, Joanna E., Sue Ma, Teresa Compton, and Kai Lin. "Combinations of Cyclophilin Inhibitor NIM811 with Hepatitis C Virus NS3-4A Protease or NS5B Polymerase Inhibitors Enhance Antiviral Activity and Suppress the Emergence of Resistance." Antimicrobial Agents and Chemotherapy 52, no. 9 (June 30, 2008): 3267–75. http://dx.doi.org/10.1128/aac.00498-08.
Повний текст джерелаАнотація:
ABSTRACT Chronic hepatitis C virus (HCV) infection remains a major global health burden while current interferon-based therapy is suboptimal. Efforts to develop more effective antiviral agents mainly focus on two viral targets: NS3-4A protease and NS5B polymerase. However, resistant mutants against these viral specific inhibitors emerge quickly both in vitro and in patients, particularly in the case of monotherapy. An alternative and complementary strategy is to target host factors such as cyclophilins that are also essential for viral replication. Future HCV therapies will most likely be combinations of multiple drugs of different mechanisms to maximize antiviral activity and to suppress the emergence of resistance. Here, the effects of combining a host cyclophilin inhibitor NIM811 with other viral specific inhibitors were investigated in vitro using HCV replicon. All of the combinations led to more pronounced antiviral effects than any single agent, with no significant increase of cytotoxicity. Moreover, the combination of NIM811 with a nucleoside (NM107) or a non-nucleoside (thiophene-2-carboxylic acid) polymerase inhibitor was synergistic, while the combination with a protease inhibitor (BILN2061) was additive. Resistant clones were selected in vitro with these inhibitors. Interestingly, it was much more difficult to develop resistance against NIM811 than viral specific inhibitors. No cross-resistance was observed among these inhibitors. Most notably, NIM811 was highly effective in blocking the emergence of resistance when used in combination with viral protease or polymerase inhibitors. Taken together, these results illustrate the significant advantages of combining inhibitors targeting both viral and host factors as key components of future HCV therapies.
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Sumalapao, Derick Erl P. "Elucidation on the Physicochemical Properties of Potential and Clinically Approved Antiviral Drugs: A Search for Effective Therapies against SARS-CoV-2 Infection." Journal of Pure and Applied Microbiology 14, suppl 1 (May 22, 2020): 1025–34. http://dx.doi.org/10.22207/jpam.14.spl1.41.
Повний текст джерелаАнотація:
COVID-19 has been confirmed in millions of individuals worldwide, rendering it a global medical emergency. In the absence of vaccines and the unavailability of effective drugs for the SARS-CoV-2 infection, vaccine development is being continuously explored and several antiviral compounds and immunotherapies are currently being investigated. Given the high similarity in genetic identity between SARS-CoV and SARS-CoV-2, the present investigation identified the interaction between the physicochemical properties and the antiviral activity of different potential and clinically approved antiviral drugs against SARS-CoV using hierarchically weighted principal component analysis. Representative drugs from the classes of neuraminidase inhibitors, reverse transcriptase inhibitors, protease inhibitors, nucleoside analogues, and other compounds with potential antiviral activity were examined. The pharmacologic classification and the biological activity of the different antiviral drugs were described using indices, namely, rotatable bond count, molecular weight, heavy atom count, and molecular complexity (92.32% contribution rate). The physicochemical properties and inhibitory action against SARS-CoV-2 of lopinavir, chloroquine, ivermectin, and ciclesonide validated the adequacy of the current computational approach. The findings of the present study provide additional information, although further investigation is warranted to identify potential targets and establish exact mechanisms, in the emergent search and design of antiviral drug candidates and their subsequent synthesis as effective therapies for COVID-19.
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Rocha-Pereira, J., M. S. J. Nascimento, Q. Ma, R. Hilgenfeld, J. Neyts, and D. Jochmans. "The Enterovirus Protease Inhibitor Rupintrivir Exerts Cross-Genotypic Anti-Norovirus Activity and Clears Cells from the Norovirus Replicon." Antimicrobial Agents and Chemotherapy 58, no. 8 (June 2, 2014): 4675–81. http://dx.doi.org/10.1128/aac.02546-13.
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ABSTRACTPotent and safe inhibitors of norovirus replication are needed for the treatment and prophylaxis of norovirus infections. We here report that thein vitroanti-norovirus activity of the protease inhibitor rupintrivir is extended to murine noroviruses and that rupintrivir clears human cells from their Norwalk replicon after only two passages of antiviral pressure. In addition, we demonstrate that rupintrivir inhibits the human norovirus (genogroup II [GII]) protease and further explain the inhibitory effect of the molecule by means of molecular modeling on the basis of the crystal structure of the Norwalk virus protease. The combination of rupintrivir with the RNA-dependent RNA polymerase inhibitors 2′-C-methylcytidine and favipiravir (T-705) resulted in a merely additive antiviral effect. The fact that rupintrivir is active against noroviruses belonging to genogroup I (Norwalk virus), genogroup V (murine norovirus), and the recombinant 3C-like protease of a GII norovirus suggests that the drug exerts cross-genotypic anti-norovirus activity and will thus most likely be effective against the clinically relevant human norovirus strains. The design of antiviral molecules targeting the norovirus protease could be a valuable approach for the treatment and/or prophylaxis of norovirus infections.
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Kausar, Shamaila, Fahad Said Khan, Muhammad Ishaq Mujeeb Ur Rehman, Muhammad Akram, Muhammad Riaz, Ghulam Rasool, Abdul Hamid Khan, Iqra Saleem, Saba Shamim, and Arif Malik. "A review: Mechanism of action of antiviral drugs." International Journal of Immunopathology and Pharmacology 35 (January 2021): 205873842110026. http://dx.doi.org/10.1177/20587384211002621.
Повний текст джерелаАнотація:
Antiviral drugs are a class of medicines particularly used for the treatment of viral infections. Drugs that combat viral infections are called antiviral drugs. Viruses are among the major pathogenic agents that cause number of serious diseases in humans, animals and plants. Viruses cause many diseases in humans, from self resolving diseases to acute fatal diseases. Developing strategies for the antiviral drugs are focused on two different approaches: Targeting the viruses themselves or the host cell factors. Antiviral drugs that directly target the viruses include the inhibitors of virus attachment, inhibitors of virus entry, uncoating inhibitors, polymerase inhibitors, protease inhibitors, inhibitors of nucleoside and nucleotide reverse transcriptase and the inhibitors of integrase. The inhibitors of protease (ritonavir, atazanavir and darunavir), viral DNA polymerase (acyclovir, tenofovir, valganciclovir and valacyclovir) and of integrase (raltegravir) are listed among the Top 200 Drugs by sales during 2010s. Still no effective antiviral drugs are available for many viral infections. Though, there are a couple of drugs for herpesviruses, many for influenza and some new antiviral drugs for treating hepatitis C infection and HIV. Action mechanism of antiviral drugs consists of its transformation to triphosphate following the viral DNA synthesis inhibition. An analysis of the action mechanism of known antiviral drugs concluded that they can increase the cell’s resistance to a virus (interferons), suppress the virus adsorption in the cell or its diffusion into the cell and its deproteinisation process in the cell (amantadine) along with antimetabolites that causes the inhibition of nucleic acids synthesis. This review will address currently used antiviral drugs, mechanism of action and antiviral agents reported against COVID-19.
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Pardee, K. I., P. Ellis, M. Bouthillier, G. HN Towers, and C. J. French. "Plant virus inhibitors from marine algae." Canadian Journal of Botany 82, no. 3 (March 1, 2004): 304–9. http://dx.doi.org/10.1139/b04-002.
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Methanolic extracts from 30 species of marine algae were assayed for antiviral activity against Potato virus X (PVX) in local lesion assays, using Chenopodium quinoa L. as host. Extracts from six algal species (Fucus gardneri Silva, Alaria marginata Postels & Ruprecht, Ralfsia sp. (Berkeley), Codium fragile (Suringar) Hariot, Fragilaria oceanica Cleve, and Egregia menziesii (Turner) J.E. Areschoug) inhibited PVX infectivity by more than 80%. Most extracts with antiviral activity came from algae that belong to the phylum Heterokontophyta. Fractionation of a crude extract from F. gardneri resulted in identification of the polysaccharide alginate as an antiviral component. Alginate inhibited PVX infectivity by 95%, and the mode of action may be via aggregation of virus particles. The present study is the first to investigate New World algae for compounds with activity against plant viruses and the first report that extracts of F. gardneri, Ralfsia sp., and Fragilaria oceanica are sources of antiviral activity.Key words: marine algae, plant viruses, antiviral activity, alginate, polysaccharides, Fucus gardneri.
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De Clercq, E. "Antiviral therapy for human immunodeficiency virus infections." Clinical Microbiology Reviews 8, no. 2 (April 1995): 200–239. http://dx.doi.org/10.1128/cmr.8.2.200.
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Depending on the stage of their intervention with the viral replicative cycle, human immunodeficiency virus inhibitors could be divided into the following groups: (i) adsorption inhibitors (i.e., CD4 constructs, polysulfates, polysulfonates, polycarboxylates, and polyoxometalates), (ii) fusion inhibitors (i.e., plant lectins, succinylated or aconitylated albumins, and betulinic acid derivatives), (iii) uncoating inhibitors (i.e., bicyclams), (iv) reverse transcription inhibitors acting either competitively with the substrate binding site (i.e., dideoxynucleoside analogs and acyclic nucleoside phosphonates) or allosterically with a nonsubstrate binding site (i.e., non-nucleoside reverse transcriptase inhibitors), (v) integration inhibitors, (vi) DNA replication inhibitors, (vii) transcription inhibitors (i.e., antisense oligodeoxynucleotides and Tat antagonists), (viii) translation inhibitors (i.e., antisense oligodeoxynucleotides and ribozymes), (ix) maturation inhibitors (i.e., protease inhibitors, myristoylation inhibitors, and glycosylation inhibitors), and finally, (x) budding (assembly/release) inhibitors. Current knowledge, including the therapeutic potential, of these various inhibitors is discussed. In view of their potential clinical the utility, the problem of virus-drug resistance and possible strategies to circumvent this problem are also addressed.
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González-Maldonado, Pamela, Nelson Alvarenga, Alberto Burgos-Edwards, Ma Eugenia Flores-Giubi, Javier E. Barúa, Ma Cristina Romero-Rodríguez, Ricardo Soto-Rifo, et al. "Screening of Natural Products Inhibitors of SARS-CoV-2 Entry." Molecules 27, no. 5 (March 7, 2022): 1743. http://dx.doi.org/10.3390/molecules27051743.
Повний текст джерелаАнотація:
The COVID-19 pandemic has led to the search for new molecules with antiviral activity against SARS-CoV-2. The entry of the virus into the cell is one of the main targets for inhibiting SARS-CoV-2 infection. Natural products are an important source of new therapeutic alternatives against diseases. Pseudotyped viruses allow the study of SARS-CoV-2 viral entry inhibitors, and due to their simplicity, they allow the screening of a large number of antiviral candidates in Biosafety Level 2 facilities. We used pseudotyped HIV-1 with the D614G SARS-CoV-2 spike glycoprotein to test its ability to infect ACE2-expressing HEK 293T cells in the presence of diverse natural products, including 21 plant extracts, 7 essential oils, and 13 compounds from plants and fungi. The 50% cytotoxic concentration (CC50) was evaluated using the resazurin method. From these analyses, we determined the inhibitory activity of the extract of Stachytarpheta cayennensis, which had a half-maximal inhibitory concentration (IC50) of 91.65 µg/mL, a CC50 of 693.5 µg/mL, and a selectivity index (SI) of 7.57, indicating its potential use as an inhibitor of SARS-CoV-2 entry. Moreover, our work indicates the usefulness of the pseudotyped-virus system in the screening of SARS-CoV-2 entry inhibitors.
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Jones, Gregg S., Fang Yu, Ameneh Zeynalzadegan, Joseph Hesselgesser, Xiaowu Chen, James Chen, Haolun Jin, et al. "Preclinical Evaluation of GS-9160, a Novel Inhibitor of Human Immunodeficiency Virus Type 1 Integrase." Antimicrobial Agents and Chemotherapy 53, no. 3 (December 22, 2008): 1194–203. http://dx.doi.org/10.1128/aac.00984-08.
Повний текст джерелаАнотація:
ABSTRACT GS-9160 is a novel and potent inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN) that specifically targets the process of strand transfer. It is an authentic inhibitor of HIV-1 integration, since treatment of infected cells results in an elevation of two-long terminal repeat circles and a decrease of integration junctions. GS-9160 has potent and selective antiviral activity in primary human T lymphocytes producing a 50% effective concentration (EC50) of ∼2 nM, with a selectivity index (50% cytotoxic concentration/EC50) of ∼2,000. The antiviral potency of GS-9160 decreased by 6- to 10-fold in the presence of human serum. The antiviral activity of GS-9160 is synergistic in combination with representatives from three different classes of antiviral drugs, namely HIV-1 protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors. Viral resistance selections performed with GS-9160 yielded a novel pattern of mutations within the catalytic core domain of IN; E92V emerged initially, followed by L74M. While E92V as a single mutant conferred 12-fold resistance against GS-9160, L74M had no effect as a single mutant. Together, these mutations conferred 67-fold resistance to GS-9160, indicating that L74M may potentiate the resistance caused by E92V. The pharmacokinetic profile of GS-9160 in healthy human volunteers revealed that once-daily dosing was not likely to achieve antiviral efficacy; hence, the clinical development of this compound was discontinued.
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Glasky, Alvin J., William R. Roderick, and J. C. Holper. "VIRAL SYNTHETASE INHIBITORS AS ANTIVIRAL AGENTS." Annals of the New York Academy of Sciences 130, no. 1 (December 16, 2006): 412–18. http://dx.doi.org/10.1111/j.1749-6632.1965.tb12577.x.
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Serkedjieva, Julia, Lidiya Angelova, Mimi Remichkova, and Iskra Ivanova. "Proteinase inhibitors fromStreptomyces with antiviral activity." Journal of Basic Microbiology 46, no. 6 (December 2006): 504–12. http://dx.doi.org/10.1002/jobm.200510127.
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Ji, Cheng. "Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors." International Journal of Molecular Sciences 24, no. 9 (April 27, 2023): 7938. http://dx.doi.org/10.3390/ijms24097938.
Повний текст джерелаАнотація:
Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed.
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Chang, Kyeong-Ok, Yunjeong Kim, Scott Lovell, Athri Rathnayake, and William Groutas. "Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors." Viruses 11, no. 2 (February 25, 2019): 197. http://dx.doi.org/10.3390/v11020197.
Повний текст джерелаАнотація:
Proteases are a major enzyme group playing important roles in a wide variety of biological processes in life forms ranging from viruses to mammalians. The aberrant activity of proteases can lead to various diseases; consequently, host proteases have been the focus of intense investigation as potential therapeutic targets. A wide range of viruses encode proteases which play an essential role in viral replication and, therefore, constitute attractive targets for the development of antiviral therapeutics. There are numerous examples of successful drug development targeting cellular and viral proteases, including antivirals against human immunodeficiency virus and hepatitis C virus. Most FDA-approved antiviral agents are peptidomimetics and macrocyclic compounds that interact with the active site of a targeted protease. Norovirus proteases are cysteine proteases that contain a chymotrypsin-like fold in their 3D structures. This review focuses on our group’s efforts related to the development of norovirus protease inhibitors as potential anti-norovirus therapeutics. These protease inhibitors are rationally designed transition-state inhibitors encompassing dipeptidyl, tripeptidyl and macrocyclic compounds. Highly effective inhibitors validated in X-ray co-crystallization, enzyme and cell-based assays, as well as an animal model, were generated by launching an optimization campaign utilizing the initial hit compounds. A prodrug approach was also explored to improve the pharmacokinetics (PK) of the identified inhibitors.
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Herlihy, Koleen J., Joanne P. Graham, Robert Kumpf, Amy K. Patick, Rohit Duggal, and Stephanie T. Shi. "Development of Intergenotypic Chimeric Replicons To Determine the Broad-Spectrum Antiviral Activities of Hepatitis C Virus Polymerase Inhibitors." Antimicrobial Agents and Chemotherapy 52, no. 10 (August 11, 2008): 3523–31. http://dx.doi.org/10.1128/aac.00533-08.
Повний текст джерелаАнотація:
ABSTRACT To address the need for broad-spectrum antiviral activity characterization of hepatitis C virus (HCV) polymerase inhibitors, we created a panel of intergenotypic chimeric replicons containing nonstructural (NS) protein NS5B sequences from genotype 2b (GT2b), GT3a, GT4a, GT5a, and GT6a HCV isolates. Viral RNA extracted from non-GT1 HCV patient plasma was subjected to reverse transcription. The NS5B region was amplified by nested PCR and introduced into the corresponding region of the GT1b (Con-1) subgenomic reporter replicon by Splicing by Overlap Extension (SOEing) PCR. Stable cell lines were generated with replication-competent chimeras for in vitro antiviral activity determination of HCV nonnucleoside polymerase inhibitors (NNIs) that target different regions of the protein. Compounds that bind to the NNI2 (thiophene carboxylic acid) or NNI3 (benzothiadiazine) allosteric sites showed 8- to >1,280-fold reductions in antiviral activity against non-GT1 NS5B chimeric replicons compared to that against the GT1b subgenomic replicon. Smaller reductions in susceptibility, ranging from 0.2- to 33-fold, were observed for the inhibitor binding to the NNI1 (benzimidazole) site. The inhibitor binding to the NNI4 (benzofuran) site showed broad-spectrum antiviral activity against all chimeric replicons evaluated in this study. In conclusion, evaluation of HCV NNIs against intergenotypic chimeric replicons showed differences in activity spectrum for inhibitors that target different regions of the enzyme, some of which could be associated with specific residues that differ between GT1 and non-GT1 polymerases. Our study demonstrates the utility of chimeric replicons for broad-spectrum activity determination of HCV inhibitors.
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Billich, A., D. Scholz, B. Charpiot, H. Gstach, P. Lehr, P. Peichl, and B. Rosenwirth. "Potent and Orally Bioavailable HIV-1 Proteinase Inhibitors Containing the 2-aminobenzylstatine Moiety." Antiviral Chemistry and Chemotherapy 6, no. 5 (October 1995): 327–36. http://dx.doi.org/10.1177/095632029500600507.
Повний текст джерелаАнотація:
In order to design HIV proteinase inhibitors which combine antiviral potency in HIV-infected cells with good oral bioavailability, new derivatives of 2-aminobenzylstatine containing HIV-1 proteinase inhibitors were synthesized. Compounds showing the desired profile emerged from a series of modifications at the P3′ moiety of the parent inhibitor [1], and are characterized by the presence of hydroxy or methoxy substituents at the C-terminal benzylamide. The most potent congeners, compounds [15] and [19], were evaluated in more detail and proved inhibitory to HIV-1 replication in primary T4 lymphocytes with EC90 = 2.2 and 2.7 nM, respectively. They also exhibited adequate oral bioavailability in the range of [13] to 42% in mice and rats. Thus, further investigation of this type of HIV proteinase inhibitor seems warranted.
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Chan, Renee, Kin Tao, Jiqing Ye, Kevin Lui, Xiao Yang, Cong Ma, and Paul Chan. "Inhibition of Influenza Virus Replication by Oseltamivir Derivatives." Pathogens 11, no. 2 (February 11, 2022): 237. http://dx.doi.org/10.3390/pathogens11020237.
Повний текст джерелаАнотація:
Characterized by the high morbidity and mortality and seasonal surge, the influenza virus (IV) remains a major public health challenge. Oseltamivir is commonly used as a first-line antiviral. As a neuraminidase inhibitor, it attenuates the penetration of viruses through the mucus on the respiratory tract and inhibits the release of virus progeny from infected cells. However, over the years, oseltamivir-resistant strains have been detected in the IV surveillance programs. Therefore, new antivirals that circumvent the resistant strains would be of great importance. In this study, two novel secondary amine derivatives of oseltamivir CUHK326 (6f) and CUHK392 (10i), which bear heteroaryl groups of M2-S31 proton channel inhibitors, were designed, synthesized and subjected to biological evaluation using plaque assay. Influenza A virus (A/Oklahoma/447/2008, H1N1), influenza B viruses (B/HongKong/CUHK33261/2012), an oseltamivir-resistant influenza A virus (A/HongKong/CUHK71923/2009, H1N1) and an oseltamivir-resistant influenza B virus (B/HongKong/CUHK33280/2012) were included in the antiviral effect assessment compared to oseltamivir carboxylate (OC). Both novel compounds significantly reduced the plaque size of seasonal IV A and B, and performed similarly to OC at their corresponding half-maximal inhibitory concentration (IC50). CUHK392 (10i) functioned more effectively than CUHK326 (6f). More importantly, these compounds showed an inhibitory effect on the oseltamivir-resistant strain under 10 nM with selective index (SI) of >200.
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He, Xi, Shuo Quan, Min Xu, Silveria Rodriguez, Shih Lin Goh, Jiajie Wei, Arthur Fridman, et al. "Generation of SARS-CoV-2 reporter replicon for high-throughput antiviral screening and testing." Proceedings of the National Academy of Sciences 118, no. 15 (March 25, 2021): e2025866118. http://dx.doi.org/10.1073/pnas.2025866118.
Повний текст джерелаАнотація:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research and antiviral discovery are hampered by the lack of a cell-based virus replication system that can be readily adopted without biosafety level 3 (BSL-3) restrictions. Here, the construction of a noninfectious SARS-CoV-2 reporter replicon and its application in deciphering viral replication mechanisms and evaluating SARS-CoV-2 inhibitors are presented. The replicon genome is replication competent but does not produce progeny virions. Its replication can be inhibited by RdRp mutations or by known SARS-CoV-2 antiviral compounds. Using this system, a high-throughput antiviral assay has also been developed. Significant differences in potencies of several SARS-CoV-2 inhibitors in different cell lines were observed, which highlight the challenges of discovering antivirals capable of inhibiting viral replication in vivo and the importance of testing compounds in multiple cell culture models. The generation of a SARS-CoV-2 replicon provides a powerful platform to expand the global research effort to combat COVID-19.
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Afowowe, Tosin Oladipo, Yasuteru Sakurai, Shuzo Urata, Vahid Rajabali Zadeh, and Jiro Yasuda. "Topoisomerase II as a Novel Antiviral Target against Panarenaviral Diseases." Viruses 15, no. 1 (December 30, 2022): 105. http://dx.doi.org/10.3390/v15010105.
Повний текст джерелаАнотація:
Although many arenaviruses cause severe diseases with high fatality rates each year, treatment options are limited to off-label use of ribavirin, and a Food and Drug Administration (FDA)-approved vaccine is not available. To identify novel therapeutic candidates against arenaviral diseases, an RNA polymerase I-driven minigenome (MG) expression system for Lassa virus (LASV) was developed and optimized for high-throughput screening (HTS). Using this system, we screened 2595 FDA-approved compounds for inhibitors of LASV genome replication and identified multiple compounds including pixantrone maleate, a topoisomerase II inhibitor, as hits. Other tested topoisomerase II inhibitors also suppressed LASV MG activity. These topoisomerase II inhibitors also inhibited Junin virus (JUNV) MG activity and effectively limited infection by the JUNV Candid #1 strain, and siRNA knockdown of both topoisomerases (IIα and IIβ) restricted JUNV replication. These results suggest that topoisomerases II regulate arenavirus replication and can serve as molecular targets for panarenaviral replication inhibitors.
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Fehrentz, J. A., B. Chomier, E. Bignon, S. Venaud, J. C. Chermann, and D. Nisato. "HIV-1 protease inhibitors containing statine : Inhibitory potency and antiviral activity." Biochemical and Biophysical Research Communications 188, no. 2 (October 1992): 865–72. http://dx.doi.org/10.1016/0006-291x(92)91136-e.
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Chou, Sunwen, Laura C. Van Wechel, and Gail I. Marousek. "Effect of Cell Culture Conditions on the Anticytomegalovirus Activity of Maribavir." Antimicrobial Agents and Chemotherapy 50, no. 7 (July 2006): 2557–59. http://dx.doi.org/10.1128/aac.00207-06.
Повний текст джерелаАнотація:
ABSTRACT The cytomegalovirus UL97 kinase inhibitor maribavir suppressed viral growth more effectively in lung fibroblasts than in skin fibroblasts, and some cellular kinase inhibitors enhanced its antiviral activity. These effects influence the phenotypic assay of drug susceptibility and suggest the possibility of therapeutically useful combinations of maribavir and cellular kinase inhibitors.
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Divocha, Valentina, and Irina Komarevzeva. "Antiviral proteinase inhibitors of plant and animal origin." Iberoamerican Journal of Medicine 2, no. 2 (March 9, 2020): 43–48. http://dx.doi.org/10.53986/ibjm.2020.0010.
Повний текст джерелаАнотація:
Introduction: Over the past 10 years, much attention has been paid to the development of new antiviral drugs based on the suppression of the proteolytic activity of enzymes by trypsin inhibitors of plant and animal origin. Material and methods: We used a trypsin inhibitor from barley, trielin- (isolated by employees of the Agro-Industrial Institute of Selection and Genetics of the Ukrainian Academy of Sciences from the salivary glands of a dog); ovomukoid (isolated from duck eggs by employees of N, I, Bach Research Institute of Biology, Russian Academy of Sciences); Influenza virus APR 8/34 (fourth passage), adapted to the lungs of mice at a dose of 20 LD /0.1 ml, titre HA( hemagglutenin) 1:32) ,white BALB/c mice weighing 12-14 g. Infection with influenza virus and treatment with inhibitors was carried out intranasally under light ether anesthesia. Doses studied were: 0.5mg/ml; 2.5 mg/ml; 5.0 mg/ml; The treatment regimen of 10 mg/ml differed only in the initial stages (1 hour before infection, during infection and 1 hour after infection, and then 6 hours after infection, 24 hours after infection, 48 hours after infection, 72 hours after infection and 96 hours after infection). Results and discussion: We found that an in vivo inhibitor from barley at a dose of 10 g/l delayed the development of influenza for 8 days. The ovomukoid possessed only prophylactic properties at a dose of 100 gamma / ml. With an increase in dose, it was toxic to animals. Trielin at a dose of 10 g/l had a pronounced therapeutic effect in influenza and was not toxic. The presence of hemagglutinin influenza virus in the lungs of treated mice was observed only on the 10th day after infection; 40% of the animals remained alive for 14 days (observation period).
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Zhao, Xiujuan, Yanyan Wang, Qinghua Cui, Ping Li, Lin Wang, Zinuo Chen, Lijun Rong, and Ruikun Du. "A Parallel Phenotypic Versus Target-Based Screening Strategy for RNA-Dependent RNA Polymerase Inhibitors of the Influenza A Virus." Viruses 11, no. 9 (September 5, 2019): 826. http://dx.doi.org/10.3390/v11090826.
Повний текст джерелаАнотація:
Influenza A virus infections cause significant morbidity and mortality, and novel antivirals are urgently needed. Influenza RNA-dependent RNA polymerase (RdRp) activity has been acknowledged as a promising target for novel antivirals. In this study, a phenotypic versus target-based screening strategy was established to identify the influenza A virus inhibitors targeting the virus RNA transcription/replication steps by sequentially using an RdRp-targeted screen and a replication-competent reporter virus-based approach using the same compounds. To demonstrate the utility of this approach, a pilot screen of a library of 891 compounds derived from natural products was carried out. Quality control analysis indicates that the primary screen was robust for identification of influenza A virus inhibitors targeting RdRp activity. Finally, two hit candidates were identified, and one was validated as a putative RdRp inhibitor. This strategy can greatly reduce the number of false positives and improve the accuracy and efficacy of primary screening, thereby providing a powerful tool for antiviral discovery.