Document 0694
 DOCN  M9590694
 TI    A peptide inhibitor of hiv-1 integrase from a combinatorial library.
 DT    9509
 AU    Lutzke RAP; Eppens NA; Weber P; Plasterk RHA; Houghten RA; The
       Netherlands Cancer Institute, Amsterdam
 SO    NIH Conf Retroviral Integrase. 1995 Jan 19-20;:(Participants' abstracts
       and posters, abstract no. 5a). Unique Identifier : AIDSLINE
       AIDS/95920025
 AB    The HIV integrase (IN) protein is potentially a good target for
       antiviral strategies, because retroviral DNA integration is essential
       for HIV replication and IN is required for integration of viral cDNA.
       Traditionally, drug lead compounds are derived from natural origins. For
       the source of potential drugs one relies on the variety resulting from
       molecular evolution. Alternatively, it is possible to generate a large
       repertoire of compounds synthetically and the concept of combinatorial
       libraries relies on the iterated synthesis of complex molecules from
       limited building blocks (e.g. nucleic acids, amino acids). Hereby, the
       source of potential drugs relies on the variety due to generation of
       molecular diversity. In order to identify an inhibitor of HIV IN we
       screened a synthetic peptide combinatorial library' (SPCL; Houghten et
       al. '91; Nature; 354;-84-86). This SPCL consists of 52 million
       hexapeptides in solution, each in equimolar representation. Along an
       iterative selection process the strongest hexapeptide can be identified.
       The hexapeptide mixtures were screened in various functional IN in vitro
       assays and we found a hexapeptide with an IC50 of approximately 2 micro
       M. Further studies suggest that the peptide acts on the conserved
       central catalytic domain of the IN protein, because (i) the
       disintegration reaction of IN50-237 was inhibited and (ii) the peptide
       inhibits IN proteins of HIV- 1, HIV-2, FIV and MLV, confirming that a
       conserved IN domain is targeted. Additional characterization of the
       hexapeptide and the mode of IN inhibition will be presented.
       Identification of a hexapeptide inhibiting IN activities proofs (1) the
       concept for the approach of combinatorial libraries for a HIV enzyme and
       could therefore be used as a lead for further modifications of the
       peptide. (2) The inhibitory peptide is not only interesting for
       development of antiviral drugs, but could also be used as tool for
       mechanistic and structural studies.
 DE    Bacterial Proteins/GENETICS/METABOLISM  Bacteriophage mu/GENETICS
       Catalysis  DNA/GENETICS/*METABOLISM  *DNA Insertion Elements
       DNA-Binding Proteins/GENETICS/METABOLISM  Hydrolysis  Mutation  MEETING
       ABSTRACT

       SOURCE: National Library of Medicine.  NOTICE: This material may be
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