Protease-mediated enzymatic hydrolysis and activation of aryl phosphoramidate derivatives of stavudine

Several proteases are capable of hydrolyzing the aryl substituted phosphoramidate derivatives of stavudine resulting in the formation of the active metabolite, alaninyl d4T monophosphate. Subtilisin Protease A, Subtilisin Griseus, Subtilisin Carlsberg, Papaya, Bacillus were amongst the most effectiv...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2005-05, Vol.40 (5), p.452-466
Main Authors: Venkatachalam, T.K., Samuel, P., Qazi, S., Uckun, F.M.
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacokinetics
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Biotransformation
Dideoxynucleotides
Distereoisomers
HIV
Hydrolysis
Magnetic Resonance Spectroscopy
Mechanism
Medical sciences
Peptide Hydrolases - metabolism
Pharmacology. Drug treatments
Phosphoric Acids - chemical synthesis
Phosphoric Acids - chemistry
Phosphoric Acids - pharmacokinetics
Prodrugs - pharmacokinetics
Proteases
Spectrophotometry, Ultraviolet
Stampidine
Stavudine - analogs & derivatives
Stavudine - chemical synthesis
Stavudine - metabolism
Stavudine - pharmacokinetics
Stereoisomerism
Thymidine Monophosphate - analogs & derivatives
Thymidine Monophosphate - metabolism
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Summary:Several proteases are capable of hydrolyzing the aryl substituted phosphoramidate derivatives of stavudine resulting in the formation of the active metabolite, alaninyl d4T monophosphate. Subtilisin Protease A, Subtilisin Griseus, Subtilisin Carlsberg, Papaya, Bacillus were amongst the most effective proteases in hydrolyzing stavudine derivatives and specificity of their activity was confirmed using several protease inhibitors to block the hydrolysis of these phosphoramidate derivatives. We found that these proteases exhibit chiral selectivity at the phosphorus center of stavudine derivatives. Our results indicate that cellular proteases may be responsible for the activation of these phosphoramidate derivatives. In addition, we show that the enzymatic hydrolysis takes place at the carboxymethyl ester side chain of these pro-drugs and the direct attack on the phosphorus center by these enzymes does not occur. Finally, we describe a novel activation pathway hitherto unknown for the activation and viral inhibitory characteristic shown by these phosphoramidate derivatives of stavudine.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2004.11.015