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Nucleotide Analogues as Inhibitors of Viral Polymerases

By Jingyue Ju, Shiv Kumar, Xiaoxu Li, Steffen Jockusch, James J. Russo

Posted 31 Jan 2020
bioRxiv DOI: 10.1101/2020.01.30.927574

Coronaviruses such as the newly discovered virus from Wuhan, China, 2019-nCoV, and the viruses that cause SARS and MERS, have resulted in regional and global public health emergencies. Based on our molecular insight that the hepatitis C virus and the coronavirus use a similar viral genome replication mechanism, we reasoned that the FDA-approved drug EPCLUSA (Sofosbuvir/Velpatasvir) for the treatment of hepatitis C will also inhibit the above coronaviruses, including 2019-nCoV. To develop broad spectrum anti-viral agents, we further describe a novel strategy to design and synthesize viral polymerase inhibitors, by combining the ProTide Prodrug approach used in the development of Sofosbuvir with the use of 3′-blocking groups that we have previously built into nucleotide analogues that function as polymerase terminators.

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