ISSN:
1573-3904
Keywords:
acyl migration-type prodrug
;
anti-HIV drug
;
conjugate of HIV protease inhibitor with RT inhibitor
;
HIV protease inhibitor
;
KNI compound
;
substrate transition state analog
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract The human immunodeficiency virus (HIV) contains an aspartic protease known to be essential for retroviral maturation and replication. Based on the transition state for substrate processing, we designed and synthesized a novel class of HIV-1 protease inhibitors containing an unnatural amino acid, allophenylnorstatine (i.e. (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid), with a hydroxymethylcarbonyl (HMC) isostere. The stereochemistry of the hydroxyl group was important for enzyme inhibition and the HMC group interacted efficiently with the aspartic acid carboxyl groups of the HIV-1 protease active site in essentially the same hydrogen bonding mode as the transition state. Small dipeptide-based HIV-1 protease inhibitors containing the HMC isostere were studied. Since some of these inhibitors showed low solubility in water, we designed a novel class of 'O→N intramolecular acyl migration'-type prodrugs of HIV-1 protease inhibitors for solubilization. Furthermore, we designed and synthesized a novel prodrug-type anti-HIV agent – the conjugate of a peptidomimetic HIV-1 protease inhibitor containing a free carboxylic acid with a nucleoside reverse transcriptase inhibitor. These studies may be useful in anti-HIV drug development.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1008944023236
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