tetano
Editor, Senior Moderator
Sci Rep
. 2020 Oct 6;10(1):16577.
doi: 10.1038/s41598-020-73641-9.
Sofosbuvir terminated RNA is more resistant to SARS-CoV-2 proofreader than RNA terminated by Remdesivir
Steffen Jockusch[SUP] 1 2 [/SUP], Chuanjuan Tao[SUP] 1 3 [/SUP], Xiaoxu Li[SUP] 1 3 [/SUP], Minchen Chien[SUP] 1 3 [/SUP], Shiv Kumar[SUP] 1 3 [/SUP], Irina Morozova[SUP] 1 3 [/SUP], Sergey Kalachikov[SUP] 1 3 [/SUP], James J Russo[SUP] 1 3 [/SUP], Jingyue Ju[SUP] 4 5 6 [/SUP]
Affiliations
Abstract
SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.
. 2020 Oct 6;10(1):16577.
doi: 10.1038/s41598-020-73641-9.
Sofosbuvir terminated RNA is more resistant to SARS-CoV-2 proofreader than RNA terminated by Remdesivir
Steffen Jockusch[SUP] 1 2 [/SUP], Chuanjuan Tao[SUP] 1 3 [/SUP], Xiaoxu Li[SUP] 1 3 [/SUP], Minchen Chien[SUP] 1 3 [/SUP], Shiv Kumar[SUP] 1 3 [/SUP], Irina Morozova[SUP] 1 3 [/SUP], Sergey Kalachikov[SUP] 1 3 [/SUP], James J Russo[SUP] 1 3 [/SUP], Jingyue Ju[SUP] 4 5 6 [/SUP]
Affiliations
- PMID: 33024223
- DOI: 10.1038/s41598-020-73641-9
Abstract
SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.