Structure of replicating SARS-CoV-2 polymerase

Hillen, Hauke S.; Kokić, Goran; Farnung, Lucas; Dienemann, Christian; Tegunov, Dimitry; Cramer, Patrick

doi:10.1101/2020.04.27.063180

Cited by 93 publications

(200 citation statements)

References 34 publications

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“…The field of COVID‐19 therapeutics development is moving rapidly, and while this manuscript was under review and revision, numerous publications and preprints have appeared. Structural studies have indicated possible binding sites in the SARS‐CoV‐2 RdRp for potential polymerase inhibitors 48‐52 . Given the high homology of the SARS‐CoV and SARS‐CoV‐2 RdRp active site domains, it is likely that they will bind nucleotide analogues such as Sofosbuvir in a similar way, as we have recently reported 46 .…”

Section: Resultsmentioning

confidence: 64%

Nucleotide analogues as inhibitors of SARS‐CoV Polymerase

Kumar

et al. 2020

Pharmacology Res & Perspec

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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.

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Section: Resultsmentioning

confidence: 64%

Nucleotide analogues as inhibitors of SARS‐CoV Polymerase

Kumar

et al. 2020

Pharmacology Res & Perspec

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“…Although retroviruses such as HIV use reverse transcriptase (estimated error rate at 10 −3 misincorporations per nucleotide position per genome replication) during their replication [ 74 ], SARS-CoV-2 uses a higher-fidelity RdRp (with an estimated error rate of 10 −4 to 10 −5 misincorporations per nucleotide position per genome replication) [ 75 ]. Hence, SARS-CoV-2 may be less prone to incorporate mutations [ 76 ]. However, a broad mutation spectrum of SARS-CoV-2 has been observed, which could lead to vaccine and drug resistance [ 77.…”

Section: Challenges In the Successful Development Of Neutralizing Antmentioning

confidence: 99%

Fruitful Neutralizing Antibody Pipeline Brings Hope To Defeat SARS-Cov-2

Renn

et al. 2020

Trends in Pharmacological Sciences

114

129

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With the recent spread of severe acute respiratory syndrome coronavirus (SARS-CoV-2)_ infecting >16 million people worldwide as of 28 July 2020, causing >650 000 deaths, there is a desperate need for therapeutic agents and vaccines. Building on knowledge of previous outbreaks of SARS-CoV-1 and Middle East respiratory syndrome (MERS), the development of therapeutic antibodies and vaccines against coronavirus disease 2019 (COVID-19) is taking place at an unprecedented speed. Current efforts towards the development of neutralizing antibodies against COVID-19 are summarized. We also highlight the importance of a fruitful antibody development pipeline to combat the potential escape plans of SARS-CoV-2, including somatic mutations and antibody-dependent enhancement (ADE).

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“…SARS-CoV-2 is an enveloped, pleomorphic or spherical shaped positive sense RNA virus having varying genome length of around 30 kb with a 5′- cap structure and 3′- poly A tail with an arrangement as 5′-replicase open reading frame (ORF) 1ab-spike( S )-envelope( E )-membrane(M)-N-3′ [ 13 , 14 ]. Population genetics analysis of 103 SARS-CoV-2 genomes indicate that these viruses have evolved into two major lineages namely the more prevalent CT haplotype or the L lineage and the TC haplotype also called the S lineage [ 15 ].…”

Section: Structure and Pathogenesis Of Sars-cov-2mentioning

confidence: 99%