Why the study?
The SARS-CoV-2 RdRp complex is a proven antiviral drug target, motivating the identification of antivirals coterminously targeting the interactions of nsp7 and nsp8 with nsp12 as well as the active site of nsp12.
Fangchinoline, cepharanthine, and sennoside B were identified as potential antivirals targeting multiple sites of the SARS-CoV-2 RdRp complex in vitro.
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In silico RdRp hits require experimental validation; leaves open any clinical antiviral role.
SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) complex consisting of nsp12, nsp7, and nsp8 as the key enzyme for viral genome replication and is a proven antiviral drug target. In this study, molecular interactions of nsp7 and nsp8 with nsp12 and the active site of nsp12 were coterminously targeted using in-silico screening of small molecule libraries to identify potential antivirals. Surface plasmon resonance (SPR) based assay using purified nsp7 and nsp8 proteins was developed, and the binding of identified molecules to targets was validated. The antiviral efficacy of identified small molecules was evaluated using cell-based assays, and potent antiviral effect with EC 50 values of 0.56 μM, 0.73 μM, and 2.8 μM was demonstrated by fangchinoline, cepharanthine, and sennoside B, respectively. Further in vivo, investigation using hACE2 mice is being conducted. This is the first study that targets multiple sites in the RdRp complex of SARS-CoV-2 using a structure-based molecular repurposing approach and suggests potential therapeutic options for emerging variants of SARS-CoV-2.
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Rani et al. (2023) studied this question.
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