Small-Molecule Dimerization Inhibitors of Wild-Type and Mutant HIV Protease:  A Focused Library Approach

We demonstrate that a focused library based on truncated, cross-linked interfacial peptides of HIV-1 protease produces effective dimerization inhibitors of the enzyme. By combining individual changes of the library into a single compound, we obtained a significantly more potent agent and found that...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2004-08, Vol.126 (32), p.9886-9887
Main Authors: Shultz, Michael D, Ham, Young-Wan, Lee, Song-Gil, Davis, David A, Brown, Cara, Chmielewski, Jean
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Binding Sites
Biological and medical sciences
Dimerization
Drug Resistance, Viral - genetics
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
General aspects, investigation methods
HIV Protease - genetics
HIV Protease - metabolism
HIV Protease Inhibitors - chemical synthesis
HIV Protease Inhibitors - chemistry
HIV Protease Inhibitors - pharmacology
Human immunodeficiency virus 1
Humans
Kinetics
Models, Molecular
Mutation
Structure-Activity Relationship
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Summary:We demonstrate that a focused library based on truncated, cross-linked interfacial peptides of HIV-1 protease produces effective dimerization inhibitors of the enzyme. By combining individual changes of the library into a single compound, we obtained a significantly more potent agent and found that an additive increase in inhibitor efficacy was obtained. The good activity of library members against an active-site drug-resistant protease mutant bodes well for dimerization inhibition as a complementary method to targeting the active site.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja048139n