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Structural Similarity of SARS-CoV2 M^pro and HCV NS3/4A Proteases Suggests New Approaches for Identifying Existing Drugs Useful as COVID-19 Therapeutics.

ABSTRACT: During the current COVID-19 pandemic more than 160,000 people have died worldwide as of mid-April 2020, and the global economy has been crippled. Effective control of the SARS-CoV2 virus that causes the COVID-19 pandemic requires both vaccines and antivirals. Antivirals are particularly crucial to treat infected people during the period of time that an effective vaccine is being developed and deployed. Because the development of specific antiviral drugs can take a considerable length of time, an important approach is to identify existing drugs already approved for use in humans which could be repurposed as COVID-19 therapeutics. Here we focus on antivirals directed against the SARS-CoV2 M^pro protease, which is required for virus replication. A structural similarity search showed that the Hepatitis C virus (HCV) NS3/4A protease has a striking three-dimensional structural similarity to the SARS-CoV2 M^pro protease, particularly in the arrangement of key active site residues. We used virtual docking predictions to assess the hypothesis that existing drugs already approved for human use or clinical testing that are directed at the HCV NS3/4A protease might fit well into the active-site cleft of the SARS-CoV2 protease (M^pro). AutoDock docking scores for 12 HCV protease inhibitors and 9 HIV-1 protease inhibitors were determined and compared to the docking scores for an ?-ketoamide inhibitor of M^pro, which has recently been shown to inhibit SARS-CoV2 virus replication in cell culture. We identified eight HCV protease inhibitors that bound to the M^pro active site with higher docking scores than the ?-ketoamide inhibitor, suggesting that these protease inhibitors may effectively bind to the M^pro active site. These results provide the rationale for us to test the identified HCV protease inhibitors as inhibitors of the SARS-CoV2 protease, and as inhibitors of SARS-CoV2 virus replication. Subsequently these repurposed drugs could be evaluated as COVID-19 therapeutics.

SUBMITTER: Bafna K

PROVIDER: S-EPMC7263768 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Structural Similarity of SARS-CoV2 M<sup>pro</sup> and HCV NS3/4A Proteases Suggests New Approaches for Identifying Existing Drugs Useful as COVID-19 Therapeutics.

Bafna Khushboo K Krug Robert M RM Montelione Gaetano T GT

ChemRxiv : the preprint server for chemistry 20200421

During the current COVID-19 pandemic more than 160,000 people have died worldwide as of mid-April 2020, and the global economy has been crippled. Effective control of the SARS-CoV2 virus that causes the COVID-19 pandemic requires both vaccines and antivirals. Antivirals are particularly crucial to treat infected people during the period of time that an effective vaccine is being developed and deployed. Because the development of specific antiviral drugs can take a considerable length of time, an ...[more]

PMID: 32511291

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Project description:BackgroundHepatitis C is a treatment-resistant disease affecting millions of people worldwide. The hepatitis C virus (HCV) genome is a single-stranded RNA molecule. After infection of the host cell, viral RNA is translated into a polyprotein that is cleaved by host and viral proteinases into functional, structural and non-structural, viral proteins. Cleavage of the polyprotein involves the viral NS3/4A proteinase, a proven drug target. HCV mutates as it replicates and, as a result, multiple emerging quasispecies become rapidly resistant to anti-virals, including NS3/4A inhibitors.Methodology/principal findingsTo circumvent drug resistance and complement the existing anti-virals, NS3/4A inhibitors, which are additional and distinct from the FDA-approved telaprevir and boceprevir α-ketoamide inhibitors, are required. To test potential new avenues for inhibitor development, we have probed several distinct exosites of NS3/4A which are either outside of or partially overlapping with the active site groove of the proteinase. For this purpose, we employed virtual ligand screening using the 275,000 compound library of the Developmental Therapeutics Program (NCI/NIH) and the X-ray crystal structure of NS3/4A as a ligand source and a target, respectively. As a result, we identified several novel, previously uncharacterized, nanomolar range inhibitory scaffolds, which suppressed of the NS3/4A activity in vitro and replication of a sub-genomic HCV RNA replicon with a luciferase reporter in human hepatocarcinoma cells. The binding sites of these novel inhibitors do not significantly overlap with those of α-ketoamides. As a result, the most common resistant mutations, including V36M, R155K, A156T, D168A and V170A, did not considerably diminish the inhibitory potency of certain novel inhibitor scaffolds we identified.Conclusions/significanceOverall, the further optimization of both the in silico strategy and software platform we developed and lead compounds we identified may lead to advances in novel anti-virals.

Project description:We have investigated the ability of hepatitis C virus non-structural (NS) 3/4A-DNA-based vaccines to activate long-term cell-mediated immune responses in mice. Wild-type and synthetic codon optimized (co) NS3/4A DNA vaccines have previously been shown to be immunogenic in mice, rabbits and humans, although we have very poor knowledge about the longevity of the immune responses primed. We therefore analyzed the functionality of primed NS3/4A-specific immune responses in BALB/c (H-2(d)) and/or C57BL/6J (H-2(b)) mice 1, 2, 3, 4, 6, 12 and 16 months after the last immunization. Mice were immunized one, two, three or four times using gene gun delivery to the skin or by intramuscular administration. Immunological responses after immunization were monitored by protection against in vivo challenge of NS3/4A-expressing syngeneic tumor cells. In addition, functionality of the NS3/4A-specific T cells was analyzed by a standard cytotoxicity assay. First, we identified a new unique murine H-2(d)-restricted NS3/4A cytotoxic T lymphocyte (CTL) epitope, which enabled us to study the epitope-specific immune responses. Our results show that the coNS3/4A vaccine was highly immunogenic by determination of interferon-?/tumor necrosis factor-? production and lytic cytotoxic T cells, which could efficiently inhibit in vivo tumor growth. Importantly, we showed that one to four monthly immunizations protected mice from tumor development when challenged up to 16 months after the last immunization. When determining the functionality of NS3/4A-specific T cells in vitro, we showed detectable lytic activity up to 12 months after the last immunization. Thus, NS3/4A-based DNA vaccines activate potent cellular immune responses that are present and function in both BALB/c and C57BL/6J mice up to 12-16 months after the last immunization. The induction of long-term immunity after NS3/4A DNA immunization has not been shown previously and supports the use of NS3/4A in hepatitis C virus vaccine compositions.

Dataset Information

Structural Similarity of SARS-CoV2 M^pro and HCV NS3/4A Proteases Suggests New Approaches for Identifying Existing Drugs Useful as COVID-19 Therapeutics.

Publications

Structural Similarity of SARS-CoV2 M<sup>pro</sup> and HCV NS3/4A Proteases Suggests New Approaches for Identifying Existing Drugs Useful as COVID-19 Therapeutics.

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Dataset Information

Structural Similarity of SARS-CoV2 Mpro and HCV NS3/4A Proteases Suggests New Approaches for Identifying Existing Drugs Useful as COVID-19 Therapeutics.

Publications

Structural Similarity of SARS-CoV2 M<sup>pro</sup> and HCV NS3/4A Proteases Suggests New Approaches for Identifying Existing Drugs Useful as COVID-19 Therapeutics.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Structural Similarity of SARS-CoV2 M^pro and HCV NS3/4A Proteases Suggests New Approaches for Identifying Existing Drugs Useful as COVID-19 Therapeutics.