Drug resistance remains a major problem in combating HIV infection, but a different approach to drug development could be the answer.
Current viral inhibitors target the HIV-1 protease function with a competitive mechanism. Writing in the BJ ChemBio Knowledge Environment of the Biochemical Journal, Max Chang and colleagues from the Scripps Research Institute, La Jolla, suggest that pharmaceutical companies look at compounds that use an allosteric non-competitive mechanism of inhibition.
The scientists examined 44 000 compounds that have already been shown to be effective at disrupting protein-protein and protein-nucleic acid interfaces and identified a compound which inhibits wild-type HIV-1 protease, as well as a drug-resistant form of protease.
Guy Salvesen, Vice Chair, The Americas, for the Biochemical Journal, said: "A major problem that plagues efficient pharmaceutical therapy is the poor selectivity of, and development of resistance to, drugs that target enzyme active sites. This approach represents a vast majority of drug development efforts for not only AIDS, but also for cancer and inflammatory diseases. The mindset of pharmaceutical chemists needs to be changed to explore more productive areas, and the paper by Max Chang and his colleagues provides a paradigm-shifting approach that, while still in its early days, would well be heeded by pharmaceutical companies."
Identification of broad-based HIV-1 protease inhibitors from combinatorial libraries.
Max W. Chang, Michael J. Giffin, Rolf Muller, Jeremiah Savage, Ying C. Lin, Sukwon Hong, Wei Jin, Landon R. Whitby, John H. Elder, Dale L. Boger, Bruce E. Torbett.
Biochemical Journal, 2010; 429 (3): 527 – 532 DOI: 10.1042/BJ20091645
Link to Bio Journal abstract