2'-C-Methyl branched pyrimidine ribonucleoside analogues: potent inhibitors of RNA virus replication.

Benzaria, Samira; Bardiot, Dorothée; Bouisset, Tony; Counor, Clément; Rabeson, Céline; Pierra, Claire; Storer, Richard; Loi, Anna Giulia; Cadeddu, Alessandra; Mura, Massimo; Musiu, Chiara; Liuzzi, Michel; Loddo, Roberta; Bergelson, Svetlana; Bichko, Vadim; Bridges, Edward; Cretton-Scott, Erika; Mao, John; Sommadossi, Jean-Pierre; Seifer, Maria; Standring, David; Tausek, Michele; Gosselin, Gilles; La Colla, Paolo

RNA viruses are the agents of numerous widespread and often severe diseases. Their unique RNA-dependent RNA polymerase (RDRP) is essential for replication and, thus, constitutes a valid target for the development of selective chemotherapeutic agents. In this regard, we have investigated sugar-modified ribonucleoside analogues as potential inhibitors of the RDRP. Title compounds retain 'natural' pyrimidine bases, but possess a beta-methyl substituent at the 2'-position of the D- or L-ribose moiety. Evaluation against a broad range of RNA viruses, either single-stranded positive (ssRNA+), single-stranded negative (ssRNA-) or double-stranded (dsRNA), revealed potent activities for D-2'-C-methyl-cytidine and -uridine against ssRNA+, and dsRNA viruses. None of the L-enantiomers were active. Moreover, the 5'-triphosphates of the active D-enantiomers were found to inhibit the bovine virus diarrhoea virus polymerase. Thus, the 2'-methyl branching of natural pyrimidine ribonucleosides transforms physiological molecules into potent, broad-spectrum antiviral agents that merit further development.