Deoxythreosyl phosphonate nucleosides as selective anti-HIV agents.
Out of a series of eight new phosphonate nucleosides with an l-threose and an l-2-deoxythreose sugar moiety, two new compounds were identified (PMDTA and PMDTT) that showed potent anti-HIV-1 (HIV-2) activity [EC50 = 2.53 microM (PMDTA) and 6.59 microM (PMDTT)], while no cytoxicity was observed at the highest concentration tested [CC50 > 316 microM (PMDTA) and > 343 microM (PMDTT)]. The kinetics of incorporation of PMDTA into DNA (using the diphosphate of PMDTA as substrate and HIV-1 reverse transcriptase as catalyst) was similar to the kinetics observed for dATP, while the diphosphate of PMDTA was a very poor substrate for DNA polymerase alpha. The incorporated PMDTA fits very well in the active site pocket of HIV-1 reverse transcriptase.
Wu
Tongfei
T
Laboratories of Medicinal Chemistry and Virology, Rega Institute for Medical Research, Minderbroedersstraat 10, Leuven, Belgium.
Froeyen
Matheus
M
Kempeneers
Veerle
V
Pannecouque
Christophe
C
Wang
Jing
J
Busson
Roger
R
De Clercq
Erik
E
Herdewijn
Piet
P
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004256:DNA Polymerase I / Q000378:metabolism; D006678:HIV / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D013329:Structure-Activity Relationship; D013780:Tetroses / Q000737:chemistry* / Q000494:pharmacology
D019380:Anti-HIV Agents; D009705:Nucleosides; D063065:Organophosphonates; D013780:Tetroses; D004247:DNA; D012194:RNA-Directed DNA Polymerase; D004256:DNA Polymerase I; C073321:erythrose