Enzymatic hydrolysis of stampidine and other stavudine phosphoramidates in the presence of mammalian proteases.
Mammalian proteases have not been implicated in the metabolism of any nucleoside phosphoramidate prodrug. The results presented herein provide unprecedented and conclusive experimental evidence that mammalian proteases are capable of hydrolyzing stavudine phosphoramidates. Specifically, cathepsin B and Proteinase K are able to metabolize stampidine and other phosphoramidate derivatives of stavudine. Additionally, cathepsin B exhibits chiral selectivity at the phosphorus center. The elucidation of the metabolic pathways leading to activation of stampidine may provide the basis for pharmacologic interventions aimed at modulating the metabolism and thereby improving the therapeutic window of stampidine as an anti-HIV agent.
Venkatachalam
T K
TK
Department of Chemistry, Pharmaceutical Sciences and Virology, Parker Hughes Institute, 2699, Patton Road, Roseville, MN 55113, USA.
Samuel
P
P
Uckun
F M
FM
D000577:Amides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002401:Cathepsin B / Q000737:chemistry; D002417:Cattle; D054306:Dideoxynucleotides; D019286:Endopeptidase K / Q000737:chemistry; D006868:Hydrolysis; D007700:Kinetics; D015394:Molecular Structure; D010447:Peptide Hydrolases / Q000737:chemistry*; D010756:Phosphoric Acids / Q000737:chemistry* / Q000378:metabolism; D018119:Stavudine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D000577:Amides; D054306:Dideoxynucleotides; D010756:Phosphoric Acids; C472384:stampidine; D013938:Thymidine Monophosphate; C011067:phosphoramidic acid; D018119:Stavudine; D010447:Peptide Hydrolases; D019286:Endopeptidase K; D002401:Cathepsin B