Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites

The rapid global emergence of SARS-CoV-2 has been the cause of significant health concern, highlighting the immediate need for antivirals. Viral RNA-dependent RNA polymerases (RdRp) play essential roles in viral RNA synthesis, and thus remains the target of choice for the prophylactic or curative tr...

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Published in:Antiviral research 2020-06, Vol.178, p.104793-104793, Article 104793
Main Authors: Shannon, Ashleigh, Le, Nhung Thi-Tuyet, Selisko, Barbara, Eydoux, Cecilia, Alvarez, Karine, Guillemot, Jean-Claude, Decroly, Etienne, Peersen, Olve, Ferron, Francois, Canard, Bruno
Format: Article
Language:English
Subjects:
Adenosine Monophosphate - analogs & derivatives
Adenosine Monophosphate - chemistry
Adenosine Monophosphate - pharmacology
Alanine - analogs & derivatives
Alanine - chemistry
Alanine - pharmacology
Antimetabolites - chemistry
Antimetabolites - pharmacology
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Betacoronavirus - chemistry
Betacoronavirus - drug effects
Betacoronavirus - genetics
Betacoronavirus - metabolism
Catalytic Domain
Coronavirus
Coronavirus Infections - drug therapy
Coronavirus Infections - virology
Coronavirus RNA-Dependent RNA Polymerase
COVID-19
Drug Resistance, Viral
Exonuclease
Exoribonucleases - chemistry
Exoribonucleases - genetics
Exoribonucleases - metabolism
Humans
Life Sciences
Microbiology and Parasitology
Models, Molecular
Mutation
Nucleotide analogue
Pandemics
Pneumonia, Viral - drug therapy
Pneumonia, Viral - virology
Protein Conformation
Remdesivir
Resistance
RNA, Viral - chemistry
RNA, Viral - genetics
RNA-Dependent RNA polymerase
RNA-Dependent RNA Polymerase - chemistry
RNA-Dependent RNA Polymerase - genetics
RNA-Dependent RNA Polymerase - metabolism
SARS-CoV-2
Structure-Activity Relationship
Viral Nonstructural Proteins - chemistry
Viral Nonstructural Proteins - genetics
Viral Nonstructural Proteins - metabolism
Virology
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Summary:The rapid global emergence of SARS-CoV-2 has been the cause of significant health concern, highlighting the immediate need for antivirals. Viral RNA-dependent RNA polymerases (RdRp) play essential roles in viral RNA synthesis, and thus remains the target of choice for the prophylactic or curative treatment of several viral diseases, due to high sequence and structural conservation. To date, the most promising broad-spectrum class of viral RdRp inhibitors are nucleoside analogues (NAs), with over 25 approved for the treatment of several medically important viral diseases. However, Coronaviruses stand out as a particularly challenging case for NA drug design due to the presence of an exonuclease (ExoN) domain capable of excising incorporated NAs and thus providing resistance to many of these available antivirals. Here we use the available structures of the SARS-CoV RdRp and ExoN proteins, as well as Lassa virus N exonuclease to derive models of catalytically competent SARS-CoV-2 enzymes. We then map a promising NA candidate, GS-441524 (the active metabolite of Remdesivir) to the nucleoside active site of both proteins, identifying the residues important for nucleotide recognition, discrimination, and excision. Interestingly, GS-441524 addresses both enzyme active sites in a manner consistent with significant incorporation, delayed chain termination, and altered excision due to the ribose 1′-CN group, which may account for the increased antiviral effect compared to other available analogues. Additionally, we propose structural and function implications of two previously identified RdRp resistance mutations in relation to resistance against Remdesivir. This study highlights the importance of considering the balance between incorporation and excision properties of NAs between the RdRp and ExoN. •Sequence comparison of SARS-CoV and SARS-CoV-2 for nsp12 (RdRp) and nsp14 (ExoN) show near structural & functional identity.•Base & ribose modifications of GS-441524 5′-TP vs ATP point to specific discrimination mechanisms & active site residues.•Lassa virus N & SARS-CoV nsp14 ExoN domains allow modeling catalytically competent SARS-CoV-2 nsp14 Exonuclease.•RNA terminated with GS-441524 5′-MP at the 3′-end indicate a problematic accommodation at the nsp14 ExoN active site.•Anti-SARS-CoV-2 nucleoside analog design must consider balance between incorporation & excision by nsp12 & nsp14.
ISSN:0166-3542
1872-9096
DOI:10.1016/j.antiviral.2020.104793