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.

2’-C-methyl branched pyrimidine ribonucleoside analogues: potent inhibitors of RNA virus replication / BENZARIA S; BARDIOT D; BOUISSET T; COUNOR C; RABESON C; PIERRA C; STORER R; LOI AG; CADEDDU A; MURA M; MUSIU C; LIUZZI M; LODDO R; BERGELSON S; BICHKO V; BRIDGES E; CRETTON-SCOTT E; MAO J; SOMMADOSSI JP; SEIFER M; STANDRING D; TAUSEK M; GOSSELIN G; LA COLLA P. - 18:4(2007), pp. 225-242.

2’-C-methyl branched pyrimidine ribonucleoside analogues: potent inhibitors of RNA virus replication

LODDO, ROBERTA;
2007

Abstract

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.
2’-C-methylnucleosides; D-enantiomers; L-enantiomers; HCV; RNA viruses; SATE pronucletides
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11584/20796
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