Synthesis and Antiviral Activity of 2-Modified L-Nucleoside Analogues

Nucleoside analogues have been the foundation of antiviral therapy over the past few decades. D-nucleosides with natural stereochemistry occupies the lion share of the marketed antiviral agents. However, much less effort have been put towards the development of L-nucleosides as antiviral agents. Herein, our effort towards the synthesis of 2 ' -substituted L-nucleoside analogues is reported as an emerging class of antiviral agents. Biological activity of the synthesized L-nucleosided was evaluated against two viruses of importance, tick-borne encephalitis virus (TBEV) and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in adenocarcinomic human alveolar basal epithelial cells (A459) and Vero cells. Ring opening of L-2, 2 '-Anhydrouridine (2) with various nucleophiles to make several 2'-substituted L-nucleosides is the key synthetic outcome. This development has paved the way in the synthesis of many new analogues of 2'-substituted L-nucleosides for numerous applications. A straight forward synthetic protocol of 2 '-substituted-L-(pyrimidine) nucleoside using a common building block, 2, 2 '-anhydro-L-uridine were developed. Conversion of one L-nucleoside into an amidite was accomplished as utility of the protocol for subsequent solid-phase synthesis of modified oligonucleotides. The cytotoxicity and antiviral activity (against tick-borne encephalitis virus (TBEV) and SARS-CoV-2) of the synthesized 2 '-modified L-nucleosides were assessed with in-vitro assay systems using A549 and Vero cell lines.image