Intriguing Antiviral Modified Nucleosides: A Retrospective View into the Future Treatment of COVID-19

Abstract

Great pioneers of nucleic acid chemistry had elucidated nucleic acid functions and structures and developed various antiviral modified nucleoside drugs. It is possible in theory that antiviral modified nucleosides prevent viral replication by inhibiting viral polymerases. However, biological phenomena far exceed our predictions at times. We describe the characteristics of the approved antiviral modified nucleosides from an organic chemistry perspective. Also, based on our experiences and findings through the development of the HIV-1 reverse-transcriptase inhibitor “Islatravir”, we provide the practical and approximate guidelines for the drug development of antiviral modified nucleosides against COVID-19.

Synthesis of novel C-nucleoside analogues bearing an anomeric cyano and a 1,2,3-triazole nucleobase as potential antiviral agents

“…Nucleosides, as constitutive units of NA, have attracted interest of medicinal chemists who have designed and synthesized numerous analogues of these natural riboside compounds, which have proved useful as therapeutic agents, and especially as antiviral drugs. 1,2 Among those, ribavirin (RBV) 1 (Fig. 1), a nucleoside analogue bearing a non-natural 3-carbamoyl-1,2,4-triazole heterocycle as nucleobase, was discovered more than 40 years ago.…”

Treatments for COVID-19: Lessons from 2020 and new therapeutic options

“…Nucleoside analogs (NAs) have historically been primary options against emerging RNA viruses and this was no exception for SARS-CoV-2. Molnupiravir (MPV), a potent experimental NA and prodrug of the synthetic nucleoside derivative N4-hydroxycytidine, introduces copying errors during viral RNA replication [ 39 , 40 ]. Initially developed by Merck to inhibit influenza viruses [ 41 ], MPV has the advantage over RDV of being administered orally.…”

Nucleosides and emerging viruses: A new story

“… [31] , [32] , [33] Nucleobase modifications have also been extensively explored, 34 and it appears that ,for enzymatic incorporation of nucleosides, modifications at C5 of pyrimidine, and at C7 of purines are tolerated 35 as long as they maintain Watson–Crick base pairing. Other sugar or nucleobase modifications have also been correlated with antiviral activities, 36 and docking studies have helped to understand the interaction of some ribonucleosides with the RdRp of RNA viruses. 37 …”