Identification of broad-based HIV-1 protease inhibitors from combinatorial libraries
Open Access
- 14 July 2010
- journal article
- research article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 429 (3), 527-532
- https://doi.org/10.1042/bj20091645
Abstract
Clinically approved inhibitors of the HIV-1 protease function via a competitive mechanism. A particular vulnerability of competitive inhibitors is their sensitivity to increases in substrate concentration, as may occur during virion assembly, budding and processing into a mature infectious viral particle. Advances in chemical synthesis have led to the development of new high-diversity chemical libraries using rapid in-solution syntheses. These libraries have been shown previously to be effective at disrupting protein–protein and protein–nucleic acid interfaces. We have screened 44000 compounds from such a library to identify inhibitors of the HIV-1 protease. One compound was identified that inhibits wild-type protease, as well as a drug-resistant protease with six mutations. Moreover, analysis of this compound suggests an allosteric non-competitive mechanism of inhibition and may represent a starting point for an additional strategy for anti-retroviral therapy.Keywords
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