Anti-HCV, nucleotide inhibitors, repurposing against COVID-19

Original Article: Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sci. 2020 May 1;248:117477. doi: 10.1016/j.lfs.2020.117477. Epub 2020 Feb 28.

Author of summary: Marco Ranzani; Reviewer: Federica La Russa

Original Article Published on February 28th, 2020

This study aims to test anti-Hepatitis C drugs against COVID-19 RNA dependent RNA polymerase (RdRp) in silico. Specifically, the modelling of COVID-19 RdRp by sequence analysis allowed to perform in silico docking studies and to identify, already approved, inhibitors that could have an effect against COVID19 including Sofosbuvir, IDX-184, Ribavirin, and Remidisvir.

The current study aims to test anti-HCV drugs against COVID-19 RNA dependent RNA polymerase (RdRp) in silico.

 

Background

·       RNA dependent RNA polymerase (RdRp) is an essential protein for the replication of several RNA viruses, including COVID-19.

·       The active site of RdRp is highly conserved among RNA viruses, and it is highly accessible to anti-viral therapies, in particular anti-Hepatitis C (HCV) nucleotide inhibitors, some of which are already approved by the FDA.

·       Previous studies showed that some of these drugs have a low micromolar inhibitory concentration (IC50) against COVID-19 RdRp.

 

Results

·       Using the sequence of COVID-19, the authors determined high homology of RdRp with that of other coronaviruses; the highest homology was measured against SARS HCoV (90.18%)

·       A robust structural COVID-19 RdRp model is built by Swiss Model using SARS HCoV RdRp as a reference and the genomic sequence of COVID-19 RdRp, and utilized for docking studies with nucleotide inhibitors used as anti-HCV therapy.

·       The four inhibitory drugs IDX-184, Sofosbuvir, Ribavirin, and Remidisvir can bind to both COVID-19 and SARS HCoV RdRp with binding energy between −6.5 and −9.0 kcal/mol. Further, all the 4 tested compounds show lower (better) binding energies to COVID-19 RdRp compared to SARS RdRp

·       Putative residues of binding between COVID-19 RdRp are herein identified and described

·       IDX-184, Sofosbuvir, and Ribavirin can tightly bind to COVID-19 RdRp, thus potentially blocking the function of the protein, and, as a result, potentially limiting the infection. Specifically, IDX-184 showed the most promising results followed by Sofosbuvir as a potent inhibitor against the newly emerged COVID-19 strain of HCoV.

Conclusions

·       This in silico study predicts that Sofosbuvir, Ribavirin, and Remdisivir could be used against the newly emerged strain of coronavirus potentially blocking viral replication, hence the infection.

·       Further optimization of IDX-184 and Sofosbuvir could result in potent compounds able to stop the newly emergent infection.

 

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