Structure-Based Inhibition of HIV-1 Protease Activity and Viral Infectivity
The protease encoded by the HIV genome is essential for viral replication, making the enzyme an important target for the therapeutic treatment of AIDS. The structure of the HIV protease1 was used to locate compounds with molecular complementarity to the active site. The computer program DOCK2 produced a negative image of the active site cavity that was a cylindrical shape 24 Å in length and 8 Å in diameter. The image was used to search 10,000 molecules of the Cambridge Crystallographic Database for compounds that could recognize the active site and serve as competitive inhibitors of the enzyme. One of the compounds to result from the complementarity screen was haloperidol, a known antipsychotic agent. Recombinant HIV-1 and HIV-2 proteases were expressed and purified from E. coli 3 and 5. cerevisiae,4 respectively, to assay the putative inhibitors. Haloperidol inhibits the HIV-1 and 2 proteases in a concentration-dependent fashion with a Ki of 100 μM.5 Both haloperidol and its hydroxy derivative, hydroxy-HAL, show activity against maturation of viral polypeptides in an E. coli assay system.
KeywordsHuman Immunodeficiency Virus Human Immunodeficiency Virus Type Mycophenolic Acid Active Site Cavity Viral Polypeptide
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- 3.L. M. Babé, S. Pichuantes, P. J. Barr, I. Bathurst, F. R. Masiarz and C. S. Craik, HIV-1 protease: bacterial expression, purification and characterization, Proteins and Pharmaceutical Engineering, UCLA Symposium on Molecular and Cellular Biology, 110: 71–88 (1990).Google Scholar
- 5.R. L. Des Jarlais, G. L. Seibel, I. D. Kuntz, P. S. Furth, J. C. Alvarez, P. R. Ortiz de Montellano, D. L. DeCamp, L. M. Babé and C. S. Craik, Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease, Proc. Natl. Acad. Sci. U.S.A. 87: 6644–6648 (1990).CrossRefGoogle Scholar