2'-C-Methyl branched pyrimidine ribonucleoside analogues: potent inhibitors of RNA virus replication.
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.
Benzaria
Samira
S
Laboratoire Coopératif Idenix-CNRS-Université Montpellier II, Montpellier, France.
Bardiot
Dorothée
D
Bouisset
Tony
T
Counor
Clément
C
Rabeson
Céline
C
Pierra
Claire
C
Storer
Richard
R
Loi
Anna Giulia
AG
Cadeddu
Alessandra
A
Mura
Massimo
M
Musiu
Chiara
C
Liuzzi
Michel
M
Loddo
Roberta
R
Bergelson
Svetlana
S
Bichko
Vadim
V
Bridges
Edward
E
Cretton-Scott
Erika
E
Mao
John
J
Sommadossi
Jean-Pierre
JP
Seifer
Maria
M
Standring
David
D
Tausek
Michele
M
Gosselin
Gilles
G
La Colla
Paolo
P
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D012328:RNA Viruses / Q000187:drug effects* / Q000502:physiology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides