NATURALLY-OCCURRING PROTEASE INHIBITORS POTENT AGAINST THE HUMAN-IMMUNODEFICIENCY-VIRUS

Inhibition of protease enzymes can render the human immunodeficiency v irus (HIV) non-infectious in vitro, To enhance bioavailability and pha rmacokinetic activity, 86 new blocking agents against HIV-1 protease a re derived by screening genome sequences from naturally occuring enzym es. The new agents are rank-ordered according to their chemical distan ce from a known set of HIV-protease inhibitors; the scoring methods ha ve previously demonstrated 92% success in classifying a given amino ac id sequence prior Co testing for antiviral potency. The work has: 1) g eneralized the empirical work on HIV-PR to more than double the number of published peptides for blocking PR activity; 2) rank-ordered the i nhibitors according to their chemical distance from the consensus sequ ence; 3) identified at least 28 gut enzymes with known bioavailability (>10%) in vivo; 4) classified the family groupings of protease inhibi tors in a hierarchical tree. Compared to the Library of best known pep tides, 19 of the natural sequences are closer to the consensus library than existing inhibitors. (C) 1996 Academic Press, Inc.