Nucleotide Analogues as Inhibitors of Viral Polymerases

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

: Virus-based and host-based treatment options targeting the coronavirus replication cycle. From Zumla et al (2016) Nat Rev | Drug Discovery 15:327-347. . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi. org/10.1101 org/10. /2020 One of the most important druggable targets is the RdRp. Example drugs include Gilead's sofosbuvir (which is paired with velpatasvir as the FDA-approved drug EPCLUSA), to inhibit the RNA-dependent RNA polymerase of the hepatitis C virus. Sofosbuvir, a pyrimidine nucleotide analogue (Fig. 2) with a blocked phosphate group enabling it to enter infected eukaryotic cells, is a prodrug, which is converted into its active triphosphate form by cellular enzymes (Fig. 3) . The activated drug binds in the active site of the RdRp, where it is incorporated into RNA, and due to modifications at the 2' position, inhibits further RNA chain extension and halts RNA replication. It acts as an RNA polymerase inhibitor by competing with natural ribonucleotides. Based on our insight that the hepatitis C virus and the coronavirus use a similar viral genome replication mechanism, we reasoned that the FDA-approved drug EPCLUSA for the treatment of hepatitis C will also inhibit coronaviruses, including 2019-nCoV and those responsible for SARS and MERS. There are many other RNA polymerase inhibitor drugs which are used as antivirals. A related purine nucleotide prodrug, remdesivir (Fig. 4) , was developed by Gilead to treat Ebola virus infections, though not very successfully, and is currently being considered for repositioning to treat the 2019-nCoV outbreak (https://www.fiercebiotech.com/biotech/gilead-mulls-repositioning-failed-ebola-drug-china-virus).