title: Characterization of two structurally novel HIV-1 protease inhibitors identified by rational selection.
abstract: The human immunodeficiency virus (HIV-1), associated with the AIDS (acquired immunodeficiency syndrome) epidemic, encodes an aspartyl protease that is essential for polyprotein processing in the virus (Navia et al., 1989). It has been demonstrated that inactivation of the protease either catalytically or by an inhibitor prevents infectious virion formation (Kohl et al., 1988; Darke et al., 1989). The acquired knowledge of key molecular interactions occurring between inhibitors and aspartyl proteases, as well as the structural similarities between HIV-1 protease and human renin was used to rationally select candidates for HIV-1 screening from the pool of analogs designed as renin inhibitors. A minimal number of chosen compounds were tested in an HIV-1 protease assay system. Two structurally novel peptides emerged as potent enzymatic protease inhibitors. This study highlights the selection process and characterizes the antiviral properties of the two novel analogs.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
authors.forename: C C
authors.initials: CC
authors.lastname: Humblet
authors.forename: E A
authors.initials: EA
authors.lastname: Lunney
authors.forename: R W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: C
authors.initials: C
authors.lastname: Doggett
authors.forename: R
authors.initials: R
authors.lastname: Wong
authors.forename: T K
authors.initials: TK
authors.lastname: Antonucci
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000201:enzymology; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D016333:HIV Protease / Q000187:drug effects / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000382:microbiology
chemical_list: D004151:Dipeptides; D017320:HIV Protease Inhibitors; C081886:PD 134922; C081887:PD 135390; D016333:HIV Protease