Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance
| Autor: | Helena M. B. Seth-Smith, Stefano Bassetti, Kirstine K. Søgaard, Tim Roloff, Manuel Battegay, Alexander Gensch, Leila Tamara Alexander, Michael Schweitzer, Hans H. Hirsch, Martin Siegemund, Alfredo Mari, Madlen Stange, Roland Bingisser, Julia Bielicki, Catia Marzolini, Adrian Egli, Michael Osthoff, Hans Pargger, Christian H. Nickel, Erblin Asllanaj, Gerardo Tauriello, Karoline Leuzinger, Parham Sendi, Torsten Schwede, Aurélien Emmanuel Martinez |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Microbiology (medical) medicine.drug_class QH301-705.5 In silico viruses RNA-dependent RNA polymerase 610 Medicine & health remdesivir Drug resistance Biology medicine.disease_cause Microbiology Genome Article resistance 03 medical and health sciences Negative selection chemistry.chemical_compound 0302 clinical medicine Virology RNA polymerase evolution medicine diagnostics Biology (General) genome analysis Genetics Mutation SARS-CoV-2 RNA dependent RNA polymerase 030104 developmental biology chemistry surveillance 570 Life sciences biology Antiviral drug 030217 neurology & neurosurgery |
| Zdroj: | Microorganisms, Vol 9, Iss 1094, p 1094 (2021) Microorganisms Mari, Alfredo; Roloff, Tim; Stange, Madlen; Søgaard, Kirstine K; Asllanaj, Erblin; Tauriello, Gerardo; Alexander, Leila Tamara; Schweitzer, Michael; Leuzinger, Karoline; Gensch, Alexander; Martinez, Aurélien E; Bielicki, Julia; Pargger, Hans; Siegemund, Martin; Nickel, Christian H; Bingisser, Roland; Osthoff, Michael; Bassetti, Stefano; Sendi, Parham; Battegay, Manuel; ... (2021). Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance. Microorganisms, 9(5) MDPI 10.3390/microorganisms9051094 Volume 9 Issue 5 |
| ISSN: | 2076-2607 |
| Popis: | A variety of antiviral treatments for COVID-19 have been investigated, involving many repurposed drugs. Currently, the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp, encoded by nsp12-nsp7-nsp8) has been targeted by numerous inhibitors, e.g., remdesivir, the only provisionally approved treatment to-date, although the clinical impact of these interventions remains inconclusive. However, the potential emergence of antiviral resistance poses a threat to the efficacy of any successful therapies on a wide scale. Here, we propose a framework to monitor the emergence of antiviral resistance, and as a proof of concept, we address the interaction between RdRp and remdesivir. We show that SARS-CoV-2 RdRp is under purifying selection, that potential escape mutations are rare in circulating lineages, and that those mutations, where present, do not destabilise RdRp. In more than 56,000 viral genomes from 105 countries from the first pandemic wave, we found negative selective pressure affecting nsp12 (Tajima’s D = −2.62), with potential antiviral escape mutations in only 0.3% of sequenced genomes. Potential escape mutations included known key residues, such as Nsp12:Val473 and Nsp12:Arg555. Of the potential escape mutations involved globally, in silico structural models found that they were unlikely to be associated with loss of stability in RdRp. No potential escape mutation was found in a local cohort of remdesivir treated patients. Collectively, these findings indicate that RdRp is a suitable drug target, and that remdesivir does not seem to exert high selective pressure. We anticipate our framework to be the starting point of a larger effort for a global monitoring of drug resistance throughout the COVID-19 pandemic. |
| Databáze: | OpenAIRE |
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