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The application of phosphoramidate protide technology to acyclovir confers anti-HIV inhibition
journal contribution
posted on 2023-06-08, 21:54 authored by Marco Derudas, Davide Carta, Andrea Brancale, Christophe Vanpouille, Andrea Lisco, Leonid Margolis, Jan Balzarini, Christopher McGuiganRecently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the l-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated. ACV ProTides with other amino acids, other than l-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types -1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive.
History
Publication status
- Published
Journal
Journal of Medicinal ChemistryISSN
0022-2623Publisher
American Chemical SocietyExternal DOI
Issue
17Volume
52Page range
5520-5530Department affiliated with
- Chemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2015-07-28Usage metrics
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