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A rational approach in the search for potent inhibitors against HIV proteinase
Author(s) -
Hui Kwan Y.,
Manetta Joseph V.,
Gygi Theresa,
Bowdon Bonnie J.,
Keith Kathy A.,
Shan William M.,
Lai MeiHuei T.
Publication year - 1991
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.5.11.1868985
Subject(s) - human immunodeficiency virus (hiv) , pharmacology , chemistry , computational biology , biology , virology
Synthetic peptides described as dog renin inhibitors were found to effectively inhibit the aspartyl protease of human immunodeficiency virus (HIV). The selection of oligopeptides for the HIV protease inhibition study was based on 1 ) the current strategy of inhibiting aspartyl proteases with transition state analogs, and 2 ) our previous observations regarding optimal structural differentiation at the P 2 position among human, dog, and rat renin inhibitors. In an in vitro assay system consisting of recombinant HIV protease and a synthetic decapeptide substrate (at pH 5.5), results show that HIV protease was unaffected by statine‐containing analogs carrying histidine at the P 2 position whereas analogs containing valine at the same position yielded anti‐protease IC 50 values ranging from 50 to 500 n m . As anticipated, some analogs were also shown to inhibit processing of recombinant polyprotein substrate by HIV protease in vitro. The antiviral activity of three inhibitors was studied in HIV‐infected CEM and MT‐2 cells. Results showed that one compound, Ac‐Naphthylalanyl‐Pro‐Phe‐Val‐Statine‐Leu‐Phe‐NH 2 (antiprotease IC 50 value = 0.4 μ m ), protected the infected cells effectively with IC 50 values (0.73 μ m for CEM cells and 0.88 μ m for MT‐2 cells). This antiviral effect is comparable to those obtained with AZT and ddC in parallel studies of MT‐2 cells.—Hui, K. Y.; Manetta, J. V.; Gygi, T.; Bowdon, B. J.; Keith, K. A.; Shannon, W. M.; Lai, M.‐H. T. A rational approach in the search for potent inhibitors against HIV proteinase. FASEB J. 5: 2606‐2610; 1991.