Deoxythreosyl Phosphonate Nucleosides as Selective Anti-HIV Agents
- 19 March 2005
- journal article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 127 (14) , 5056-5065
- https://doi.org/10.1021/ja043045z
Abstract
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 μM (PMDTA) and 6.59 μM (PMDTT)], while no cytoxicity was observed at the highest concentration tested [CC50 > 316 μM (PMDTA) and > 343 μM (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 α. The incorporated PMDTA fits very well in the active site pocket of HIV-1 reverse transcriptase.Keywords
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