Key result
Structural modeling indicates that GS-441524 addresses both RdRp and ExoN active sites, consistent with significant incorporation, delayed chain termination, and altered excision.
Why the study?
The rapid emergence of SARS-CoV-2 created an immediate need for antivirals, but coronaviruses present challenges for nucleoside analogue design due to an exonuclease capable of excising incorporated analogues.
Population
Derived structural models of catalytically competent SARS-CoV-2 RdRp and ExoN enzymes
Comparison
GS-441524 mapped to the nucleoside active sites of RdRp and ExoN
Design
Structural modeling study
Authors
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May guide nucleoside analog optimization against proofreading viruses; leaves open clinical translation in SARS-CoV-2.
Structural modeling suggests that the active metabolite of remdesivir (GS-441524) evades viral exonuclease activity due to its ribose 1'-CN group, explaining its antiviral efficacy against SARS-CoV-2.
Shannon et al. (2020) studied SARS-CoV-2. GS-441524 (Remdesivir active metabolite) was evaluated on Structural modeling of nucleotide recognition, discrimination, and excision. Structural modeling indicates that GS-441524 addresses both RdRp and ExoN active sites, consistent with significant incorporation, delayed chain termination, and altered excision.
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