title: The application of phosphoramidate protide technology to acyclovir confers anti-HIV inhibition.
abstract: Recently, 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.
authors: Welsh School of Pharmacy, Cardiff University, Cardiff, UK.
authors: Marco
authors: M
authors: Derudas
authors: Davide
authors: D
authors: Carta
authors: Andrea
authors: A
authors: Brancale
authors: Christophe
authors: C
authors: Vanpouille
authors: Andrea
authors: A
authors: Lisco
authors: Leonid
authors: L
authors: Margolis
authors: Jan
authors: J
authors: Balzarini
authors: Christopher
authors: C
authors: McGuigan
mesh_terms: D000212:Acyclovir / Q000737:chemistry* / Q000494:pharmacology*; D000577:Amides / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D001554:Benzene / Q000737:chemistry; D020134:Catalytic Domain; D043402:Cathepsin A / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004952:Esters / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D010756:Phosphoric Acids / Q000737:chemistry*; D018139:Simplexvirus / Q000187:drug effects
chemical_list: D000577:Amides; D000596:Amino Acids; D019380:Anti-HIV Agents; D004952:Esters; C063306:HINT1 protein, human; D009419:Nerve Tissue Proteins; D010756:Phosphoric Acids; C011067:phosphoramidic acid; D043402:Cathepsin A; D001554:Benzene; D000212:Acyclovir