title: Discovery and analysis of a series of C2-symmetric HIV-1 proteinase inhibitors derived from penicillin.
abstract: In order to identify a suitable peptide substrate for human immunodeficiency virus-1 (HIV-1) proteinase, a range of peptides from various cleavage sites within the gag-pol polyprotein were assayed by HPLC for specific cleavage. The peptide with the optimal combination of favorable kinetics and good solubility was based on the N-terminus cleavage site of HIV-1 proteinase (KQGTVSFNF*PQIT). The HPLC assay, using the above peptide, was developed into a rapid isocratic method in order to analyze inhibition kinetics. An assay suitable for high-throughput screening was developed using a radioactively labeled peptide with the same sequence, coupled to a solid phase. Using this assay, a C2-symmetric HIV-1 proteinase inhibitor derived from penicillin was discovered during random screening of a compound library. A chemical synthesis program developed this structure into a series of potent inhibitors. The lead structures were highly selective for HIV-1 proteinase with good antiviral activity in vitro against HIV and no cytotoxicity. The HPLC assay was used to demonstrate that these compounds are competitive tight-binding inhibitors of HIV-1 proteinase.
authors.affiliation: Department of Virology, Glaxo Group Research Ltd., Greenford, Middlesex, United Kingdom.
authors.forename: N M
authors.initials: NM
authors.lastname: Gray
authors.forename: J M
authors.initials: JM
authors.lastname: Cameron
authors.forename: N
authors.initials: N
authors.lastname: Cammack
authors.forename: K N
authors.initials: KN
authors.lastname: Cobley
authors.forename: D S
authors.initials: DS
authors.lastname: Holmes
authors.forename: D C
authors.initials: DC
authors.lastname: Humber
authors.forename: D C
authors.initials: DC
authors.lastname: Orr
authors.forename: C R
authors.initials: CR
authors.lastname: Penn
authors.forename: R
authors.initials: R
authors.lastname: Potter
authors.forename: S
authors.initials: S
authors.lastname: Madar
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D017320:HIV Protease Inhibitors / Q000032:analysis* / Q000494:pharmacology; D007700:Kinetics; D008969:Molecular Sequence Data; D010406:Penicillins / Q000032:analysis* / Q000494:pharmacology
chemical_list: D017320:HIV Protease Inhibitors; D010406:Penicillins