RT Journal Article
SR Electronic
T1 Structural Analysis of the Activation of Ribavirin Analogs by NDP Kinase: Comparison with Other Ribavirin Targets
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 538
OP 546
DO 10.1124/mol.63.3.538
VO 63
IS 3
A1 Gallois-Montbrun, Sarah
A1 Chen, Yuxing
A1 Dutartre, Hélène
A1 Sophys, Magali
A1 Morera, Solange
A1 Guerreiro, Catherine
A1 Schneider, Benoit
A1 Mulard, Laurence
A1 Janin, Joël
A1 Veron, Michel
A1 Deville-Bonne, Dominique
A1 Canard, Bruno
YR 2003
UL http://molpharm.aspetjournals.org/content/63/3/538.abstract
AB 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.