HIV Protease Inhibition: Limited Recent Progress and Advances in Understanding Current Pitfalls

Author(s): Fatima Rodriguez-Barrios, Federico Gago.

Journal Name: Current Topics in Medicinal Chemistry

Volume 4 , Issue 9 , 2004

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The identification of HIV-1 protease (HIVp) as a target for therapeutic intervention against AIDS was soon followed by major efforts to understand its substrate specificity, reaction kinetics and three-dimensional structure, both in the free state and in complex with a number of ligands including substrate mimics, products, and inhibitors. On the whole these studies have been extremely successful and have had a major impact on our understanding of ligand-receptor interactions and enzyme inhibition mechanisms. HIVp has also become a paradigm for the development and testing of new drug-design methodologies both in vitro and in silico. Even though thousands of potential HIVp inhibitors exhibiting amazing chemical diversity have been synthesized or identified from natural sources, only a few have turned out to be useful for human therapy. Although the alternative goal of preventing enzyme dimerization has been achieved as a proof of concept, this approach has not yet yielded a clinical candidate. The review covers the general strategies that led to some of the most useful inhibitors, the reasons for our limited success in effectively inhibiting this retroviral target in a clinical setting, current progress with second-generation inhibitors, and new avenues for research.

Keywords: hiv, hiv-1 protease (hivp, drug-design, hivp inhibitors, reverse transcriptase

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Article Details

Year: 2004
Page: [991 - 1007]
Pages: 17
DOI: 10.2174/1568026043388529
Price: $58

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