Article ; Online: Genetic conservation of SARS-CoV-2 RNA replication complex in globally circulating isolates and recently emerged variants from humans and minks suggests minimal pre-existing resistance to remdesivir.
2021 Volume 188, Page(s) 105033
Abstract: ... genetic stability of the RNA replication complex observed over time and in the recently emerged SARS-CoV-2 variants ... suggests a minimal global risk of pre-existing SARS-CoV-2 resistance to RDV. ... existing resistance to RDV and the possibility of SARS-CoV-2 genetic diversification that might impact RDV ...
| Abstract | Remdesivir (RDV) exhibits potent antiviral activity against SARS-CoV-2 and is currently the only drug approved for the treatment of COVID-19. However, little is currently known about the potential for pre-existing resistance to RDV and the possibility of SARS-CoV-2 genetic diversification that might impact RDV efficacy as the virus continue to spread globally. In this study, >90,000 SARS-CoV-2 sequences from globally circulating clinical isolates, including sequences from recently emerged United Kingdom and South Africa variants, and >300 from mink isolates were analyzed for genetic diversity in the RNA replication complex (nsp7, nsp8, nsp10, nsp12, nsp13, and nsp14) with a focus on the RNA-dependent RNA polymerase (nsp12), the molecular target of RDV. Overall, low genetic variation was observed with only 12 amino acid substitutions present in the entire RNA replication complex in ≥0.5% of analyzed sequences with the highest overall frequency (82.2%) observed for nsp12 P323L that consistently increased over time. Low sequence variation in the RNA replication complex was also observed among the mink isolates. Importantly, the coronavirus Nsp12 mutations previously selected in vitro in the presence of RDV were identified in only 2 isolates (0.002%) within all the analyzed sequences. In addition, among the sequence variants observed in ≥0.5% clinical isolates, including P323L, none were located near the established polymerase active site or sites critical for the RDV mechanism of inhibition. In summary, the low diversity and high genetic stability of the RNA replication complex observed over time and in the recently emerged SARS-CoV-2 variants suggests a minimal global risk of pre-existing SARS-CoV-2 resistance to RDV. |
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| MeSH term(s) | Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Amino Acid Substitution ; Animals ; COVID-19/epidemiology ; COVID-19/virology ; Drug Resistance, Viral ; Evolution, Molecular ; Genetic Variation ; Humans ; Mink ; Models, Molecular ; Protein Conformation ; RNA, Viral ; SARS-CoV-2/classification ; SARS-CoV-2/drug effects ; SARS-CoV-2/genetics ; SARS-CoV-2/isolation & purification ; Sequence Analysis, DNA ; Structure-Activity Relationship ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Virus Replication/genetics ; Whole Genome Sequencing ; COVID-19 Drug Treatment | |||||
| Chemical Substances | RNA, Viral ; Viral Nonstructural Proteins ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Alanine (OF5P57N2ZX) | |||||
| Language | English | |||||
| Publishing date | 2021-02-05 | |||||
| Publishing country | Netherlands | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 306628-9 | |||||
| ISSN | 1872-9096 ; 0166-3542 | |||||
| ISSN (online) | 1872-9096 | |||||
| ISSN | 0166-3542 | |||||
| DOI | 10.1016/j.antiviral.2021.105033 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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