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Inhibition of the RNA-dependent RNA Polymerase of the SARS-CoV-2 by Short Peptide Inhibitors.

ABSTRACT: The rapid proliferation of SARS-CoV-2 in COVID-19 patients has become detrimental to their lives. However, blocking the replication cycle of SARS-CoV-2 will help in suppressing the viral loads in patients, which would ultimately help in the early recovery. To discover such drugs, molecular docking, MD-simulations, and MM/GBSA approaches have been used herein to examine the role of several short ionic peptides in inhibiting the RNA binding site of the RNA-dependent RNA polymerase (RdRp). Out of the 49 tri- and tetrapeptide inhibitors studied, 8 inhibitors were found to bind RdRp strongly as revealed by the docking studies. Among these inhibitors, the Ala1-Arg2-Lys3-Asp4 and Ala1-Lys2-Lys3-Asp4 are found to make the most stable complexes with RdRp and possess the ΔG_bind of -17.41 and -14.21 kcal/mol respectively as revealed by the MD and MM/GBSA studies. Hence these peptide inhibitors would be highly potent in inhibiting the activities of RdRp. It is further found that these inhibitors can occupy the positions of the nucleotide triphosphate (NTP) insertion site, thereby inhibiting the replication of the viral genome by obstructing the synthesis of new nucleotides. Structural and energetic comparisons of these inhibitors with Remdesivir and similar nucleotide drugs show that these peptides would be more specific and hence may act as promiscuous antiviral agents against RdRp.

SUBMITTER: Pant S

PROVIDER: S-EPMC8445883 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction. The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10?years later, SARS-CoV-2 is the third coronavirus in less than 20?years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics.Aim. To identify drugs against COVID-19, we performed an in silico virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication.Methodology. Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the in silico virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the in silico virtual screen.Results. The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects.Conclusion. Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our in silico findings.

Project description:Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19) pandemic. Despite intensive and global efforts to discover and develop novel antiviral therapies, only Remdesivir has been approved as a treatment for COVID-19. Therefore, effective antiviral therapeutics are still urgently needed to combat and halt the pandemic. Viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 demonstrates high potential as a reliable target for the development of antivirals. We previously developed a cell-based assay to assess the efficiency of compounds that target SARS-CoV-2 RdRp, as well as their tolerance to viral exoribonuclease-mediated proof-reading. In our previous study, we discovered that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides specifically targets the RdRp of both respiratory syncytial virus (RSV) and influenza A virus. Thus, we hypothesize that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides may also have the ability to inhibit SARS-CoV-2 replication by targeting its RdRp activity. In this research, we test a compound library containing 103 of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides against SARS-CoV-2 RdRp, using our cell-based assay. Among these compounds, the top five candidates strongly inhibit SARS-CoV-2 RdRp activity while exhibiting low cytotoxicity and resistance to viral exoribonuclease. Compound 6-72-2a is the most promising candidate with the lowest EC50 value of 1.41 μM and highest selectivity index (CC50/EC50) (above 70.92). Furthermore, our data suggests that 4-46b and 6-72-2a also inhibit the replication of HCoV-OC43 and HCoV-NL63 virus in a dose-dependent manner. Compounds 4-46b and 6-72-2a exhibit EC50 values of 1.13 μM and 0.94 μM, respectively, on HCoV-OC43 viral replication. However, higher concentrations of these compounds are needed to effectively block HCoV-NL63 replication. Together, our findings successfully identified 4-46b and 6-72-2a as promising inhibitors against SARS-CoV-2 RdRp.

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Inhibition of the RNA-dependent RNA Polymerase of the SARS-CoV-2 by Short Peptide Inhibitors.

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