Document 0183
 DOCN  M9460183
 TI    Discovery and analysis of a series of C2-symmetric HIV-1 proteinase
       inhibitors derived from penicillin.
 DT    9404
 AU    Gray NM; Cameron JM; Cammack N; Cobley KN; Holmes DS; Humber DC; Orr DC;
       Penn CR; Potter R; Madar S; et al; Department of Virology, Glaxo Group
       Research Ltd., Greenford,; Middlesex, United Kingdom.
 SO    Anal Biochem. 1994 Jan;216(1):89-96. Unique Identifier : AIDSLINE
       MED/94182744
 AB    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.
 DE    Amino Acid Sequence  Cell Line  Chromatography, High Pressure Liquid
       HIV Protease Inhibitors/*ANALYSIS/PHARMACOLOGY  Kinetics  Molecular
       Sequence Data  Penicillins/*ANALYSIS/PHARMACOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).