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

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About: Remdesivir and SARS-CoV-2: structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	Remdesivir and SARS-CoV-2: structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites
Creator	Canard, Bruno Decroly, Etienne Selisko, Barbara Peersen, Olve Guillemot, Jean-Claude Alvarez, Karine Ferron, Francois Alvarez, C Cov, Sars Shannon, Ashleigh Eydoux, Cecilia Thi, Nhung Decroly, J.-C Ferron, O Le, Tuyet
source	Elsevier; Medline; PMC
abstract	Abstract 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.
has issue date	2020-04-10(xsd:dateTime)
bibo:doi	10.1016/j.antiviral.2020.104793
bibo:pmid	32283108
has license	els-covid
sha1sum (hex)	1e8874fb92f6e4e828b2b4e7521396f1b1132a6c
schema:url	https://doi.org/10.1016/j.antiviral.2020.104793
resource representing a document's title	Remdesivir and SARS-CoV-2: structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites
has PubMed Central identifier	PMC7151495
has PubMed identifier	32283108
schema:publication	Antiviral Res
resource representing a document's body	covid:1e8874fb92f6e4e828b2b4e7521396f1b1132a6c#body_text
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