Interface-based Design of the Favipiravir-binding Site in SARS-CoV-2 RNA-dependent RNA Polymerase Reveals Mutations Conferring Resistance to Chain Termination
Digital Object Identifier (DOI)
Favipiravir is a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp) currently being used to manage COVID-19. Accumulation of mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRp may facilitate antigenic drift, generating favipiravir resistance. Focussing on the chain-termination mechanism utilized by favipiravir, we used high-throughput interface-based protein design to generate > 100 000 designs of the favipiravir-binding site of RdRp and identify mutational hotspots. We identified several single-point mutants and designs having a sequence identity of 97%–98% with wild-type RdRp, suggesting that SARS-CoV-2 can develop favipiravir resistance with few mutations. Out of 134 mutations documented in the CoV-GLUE database, 63 specific mutations were already predicted as resistant in our calculations, thus attaining ˜ 47% correlation with the sequencing data. These findings improve our understanding of the potential signatures of adaptation in SARS-CoV-2 against favipiravir.
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Citation / Publisher Attribution
FEBS Letters, v. 595, issue 18, p. 2366-2382
Scholar Commons Citation
Padhi, Aditya K.; Dandapat, Jagneshwar; Saudagar, Prakash; Uversky, Vladimir N.; and Tripathi, Timir, "Interface-based Design of the Favipiravir-binding Site in SARS-CoV-2 RNA-dependent RNA Polymerase Reveals Mutations Conferring Resistance to Chain Termination" (2021). Molecular Medicine Faculty Publications. 898.