Substrate analog inhibitors of HIV protease will be designed and synthesized as chemotherapeutic agents for the treatment of human immunodeficiency virus, the causative agent of AIDS. Inhibitor development will encompass four stages: 1) size reduction and specificity studies to identify the smallest possible peptidic inhibitors, 2) dipeptide isostere synthesis to discover novel, transition-state replacements for the P-P' residues, 3) structure- activity studies addressing pharmacokinetics and bioavailability in order to optimize delivery of peptidic inhibitors to the target cells, and 4) synthesis of peptidomimetics which will capture the biologic essence of the peptidic inhibitors in a non-peptide compound. The successful development of HIV protease inhibitors described in this project is highly dependent on the collaborating projects and may lead to a new treatment for AIDS.

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Abbott Laboratories
North Chicago
United States
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Horne, David J; Narita, Masahiro; Spitters, Christopher L et al. (2013) Challenging issues in tuberculosis in solid organ transplantation. Clin Infect Dis 57:1473-82
Kageyama, S; Weinstein, J N; Shirasaka, T et al. (1992) In vitro inhibition of human immunodeficiency virus (HIV) type 1 replication by C2 symmetry-based HIV protease inhibitors as single agents or in combinations. Antimicrob Agents Chemother 36:926-33
Rao, J K; Erickson, J W; Wlodawer, A (1991) Structural and evolutionary relationships between retroviral and eucaryotic aspartic proteinases. Biochemistry 30:4663-71
Kempf, D J; Marsh, K C; Paul, D A et al. (1991) Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease. Antimicrob Agents Chemother 35:2209-14
Fesik, S W; Gampe Jr, R T; Eaton, H L et al. (1991) NMR studies of [U-13C]cyclosporin A bound to cyclophilin: bound conformation and portions of cyclosporin involved in binding. Biochemistry 30:6574-83
Rittenhouse, J; Turon, M C; Helfrich, R J et al. (1990) Affinity purification of HIV-1 and HIV-2 proteases from recombinant E. coli strains using pepstatin-agarose. Biochem Biophys Res Commun 171:60-6
Erickson, J; Neidhart, D J; VanDrie, J et al. (1990) Design, activity, and 2.8 A crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease. Science 249:527-33
Eaton, H L; Austin, R E; Fesik, S W et al. (1989) NMR study of the possible interaction in solution of angiotensin II with a peptide encoded by angiotensin II complementary RNA. Proc Natl Acad Sci U S A 86:9767-9