Combinatorial libraries of peptides and peptidomimetics will be used to identify individual compounds which interfere with the cleavage of natural products or synthetic substrates. Successful preliminary studies using a hexapeptide combinatorial library made up of 64 x 10 6 hexapeptides have been carried out. This initial success prompts the testing of a range of other peptide and peptidomimetic combinatorial libraries to block cleavage of an indicator substrate. An accurate, inexpensive and rapid assay has been developed at the subcontracting organization to facilitate these studies, involving the cleavage and inactivation of horseradish peroxidase (HRP) by the viral proteases. Coupled with reagents for the development of HRP-based ELISA assays, the procedure gives a quantitative measure of HRP inactivation by protease, or conversely, lack of inactivation in the presence of effective inhibitors. Compounds identified in initial analyses will then be tested for their ability to block the processing of natural substrates for the viral proteases. Ex vivo and in vivo analyses will be carried out in later phases to measure the efficacy of inhibitors developed under Phase I. This information will aid in the development of broad-based protease inhibitors for the control of lentivirus infections. PROPOSED COMMERCIAL APPLICATION: Through novel drug discovery, rapid throughput assays and a unique in vivo assay system, lead drugs will be identified that will have unique properties for therapeutics in both HIV-1 and/or FIV lentivirus infection.
Thesaurus Terms:Lentivirus, Retroviridae, endopeptidase, peptide library, protease inhibitor, virus protein enzyme substrate, feline immunodeficiency virus, horseradish peroxidase, human immunodeficiency virus, synthetic peptideNational Institute of Mental Health (NIMH)
