Anti-HIV activity of (-)-(2R,4R)-1- (2-hydroxymethyl-1,3-dioxolan-4-yl)-thymine against drug-resistant HIV-1 mutants and studies of its molecular mechanism.
(-)-(2R,4R)-1-(2-Hydroxymethyl-1,3-dioxolan-4-yl)thymine (DOT) is the first thymidine kinase-activated nucleoside that is significantly active against all of the clinically significant NRTI-resistant HIV-1 mutants, including AZT (D67N/K70R/T215Y/K219Q), Tenofovir (K65R), and Lamivudine (M184V). To understand the molecular mechanism of drug resistance and the antiviral activity of DOT against drug-resistant RTs, molecular modeling studies of DOT-TP complexed with the wild-type (WT) and mutated RT were conducted. The key reason for this interesting antiviral activity profile is the presence of a dioxolane ring.
Chu
Chung K
CK
College of Pharmacy, The University of Georgia, Athens, 30602, USA. dchu@rx.uga.edu
Yadav
Vikas
V
Chong
Youhoon H
YH
Schinazi
Raymond F
RF
D019380:Anti-HIV Agents / Q000737:chemistry*; D001665:Binding Sites; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013237:Stereoisomerism
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase