Nucleotide analogues as inhibitors of SARS‐CoV Polymerase

Abstract

SARS‐CoV‐2, a member of the coronavirus family, has caused a global public health emergency. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA‐approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS‐CoV‐2. Here, using model polymerase extension experiments, we demonstrate that the active triphosphate form of Sofosbuvir is incorporated by low‐fidelity polymerases and SARS‐CoV RNA‐dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the active triphosphate form of Sofosbuvir is not incorporated by a host‐like high‐fidelity DNA polymerase. Using the same molecular insight, we selected 3’‐fluoro‐3’‐deoxythymidine triphosphate and 3’‐azido‐3’‐deoxythymidine triphosphate, which are the active forms of two other anti‐viral agents, Alovudine and AZT (an FDA‐approved HIV/AIDS drug) for evaluation as inhibitors of SARS‐CoV RdRp. We demonstrate the ability of two of these HIV reverse transcriptase inhibitors to be incorporated by SARS‐CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS‐CoV and SARS‐CoV‐2 RdRps, we expect these nucleotide analogues would also inhibit the SARS‐CoV‐2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad‐spectrum anti‐coronavirus agents.

Repurposing Drugs, Ongoing Vaccine, and New Therapeutic Development Initiatives Against COVID-19

“…Other nucleotide/nucleoside analogs, e.g., sofosbuvir ( Gane et al., 2013 ; Appleby et al., 2015 ; Ju et al., 2020 ), and ribavirin ( Elfiky, 2020 ), were also found to be effective in inhibiting RdRp. Favipiravir, which has a structural similarity with nucleoside analogs, found to be effective in COVID-19 clinical trials ( Chen C. et al., 2020 ).…”

“…Another nucleoside analog galidesivir (BCX-4430) was found effective in several infectious diseases, including Ebola, Zika, etc., and maybe useful in COVID-19, too ( Taylor et al., 2016 ; Eyer et al., 2019 ). Similar antiviral drugs, triphosphate forms of AZT (3’-azido-3’-deoxythymidine triphosphate), and alovudine (3’-fluoro-3’-deoxythymidine triphosphate) were also predicted to inhibit SARS-CoV-2 RdRp ( Ju et al., 2020 ). The guanosine analog ribavirin not only inhibits viral RdRp by directly interfering with it but also interferes with the RNA capping by inhibiting inosine monophosphate dehydrogenase enzyme to impede guanosine production in the host cell ( Graci and Cameron, 2006 ; Khalili et al., 2020 ).…”

Existing Antiviral Options Against SARS-CoV-2 Replication in COVID-19 Patients

“…This class of existing drugs is actually nucleotide and nucleoside analogs in the form of adenine and guanine derivatives. These nucleotide analog drugs can inhibit the viral genome replication and transcription via targeting the viral RdRp, in wide range of RNA viruses [ 60 ]. RdRp plays a central role in the transcription and replication of SARS-CoV-2 RNA genome, and appears to be a primary target for the nucleotide analog antiviral inhibitors [ 61 ].…”

Therapeutic modalities and novel approaches in regenerative medicine for COVID-19

“…Other nucleotide analogues such as favipiravir (nucleoside analog), ribavirin (guanosine analog), galidesivir (adenosine analog), sofosbuvir (pyrimidine nucleotide analogue), alovudine (thymidine dideoxynucleoside analogue), Zidovudine (ZDV) (thymidine analogue), etc. are also under investigation for treatment of COVID-19 ( 29 , 64 ). Favipiravir is an RNA polymerase inhibitor for a number of RNA viruses, and is approved for treatment of influenza in China and Japan.…”