Abstract:
:Ribavirin used in therapies against hepatitis C virus (HCV) is potentially efficient against other viruses but presents a high cytotoxicity. Several ribavirin triphosphate analogs modified on the ribose moiety were synthesized and tested in vitro on the RNA polymerases of HCV, phage T7, and HIV-1 reverse transcriptase. Modified nucleotides with 2'-deoxy, 3'-deoxy, 2',3'-dideoxy, 2',3'-dideoxy-2',3'-dehydro, and 2',3'-epoxy-ribose inhibited the HCV enzyme but not the other two polymerases. They were also analyzed as substrates for nucleoside diphosphate (NDP) kinase, the enzyme responsible for the last step of the cellular activation of antiviral nucleoside analogs. An X-ray structure of NDP kinase complexed with ribavirin triphosphate was determined. It demonstrates that the analog binds as a normal substrate despite the modified base and confirms the crucial role of the 3'-hydroxyl group in the phosphorylation reaction. The 3'-hydroxyl is required for inhibition of the initiation step of RNA synthesis by HCV polymerase, and both sugar hydroxyls must be present to inhibit elongation. The 2'deoxyribavirin is the only derivative efficient in vitro against HCV polymerase and properly activated by NDP kinase.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Gallois-Montbrun S,Chen Y,Dutartre H,Sophys M,Morera S,Guerreiro C,Schneider B,Mulard L,Janin J,Veron M,Deville-Bonne D,Canard Bdoi
10.1124/mol.63.3.538keywords:
subject
Has Abstractpub_date
2003-03-01 00:00:00pages
538-46issue
3eissn
0026-895Xissn
1521-0111journal_volume
63pub_type
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