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A rational approach in the search for potent inhibitors against HIV proteinase

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 P2 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 P2 position whereas analogs containing valine at the same position yielded anti‐protease IC50 values ranging from 50 to 500 nm. 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‐NH2 (antiprotease IC50 value = 0.4 μm), protected the infected cells effectively with IC50 values (0.73 μm for CEM cells and 0.88 μm 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.