title: Small molecule functional analogs of peptides that inhibit lambda site-specific recombination and bind Holliday junctions.
abstract: Our lab has isolated hexameric peptides that are structure-selective ligands of Holliday junctions (HJ), central intermediates of several DNA recombination reactions. One of the most potent of these inhibitors, WRWYCR, has shown antibacterial activity in part due to its inhibition of DNA repair proteins. To increase the therapeutic potential of these inhibitors, we searched for small molecule inhibitors with similar activities. We screened 11 small molecule libraries comprising over nine million individual compounds and identified a potent N-methyl aminocyclic thiourea inhibitor that also traps HJs formed during site-specific recombination reactions in vitro. This inhibitor binds specifically to protein-free HJs and can inhibit HJ resolution by RecG helicase, but only showed modest growth inhibition of bacterial with a hyperpermeable outer membrane; nonetheless, this is an important step in developing a functional analog of the peptide inhibitors.
authors.affiliation: Department of Biology and Center for Microbial Sciences, San Diego State University, San Diego, CA 92182-4614, USA.
authors.forename: Dev K
authors.initials: DK
authors.lastname: Ranjit
authors.forename: Marc C
authors.initials: MC
authors.lastname: Rideout
authors.forename: Adel
authors.initials: A
authors.lastname: Nefzi
authors.forename: John M
authors.initials: JM
authors.lastname: Ostresh
authors.forename: Clemencia
authors.initials: C
authors.lastname: Pinilla
authors.forename: Anca M
authors.initials: AM
authors.lastname: Segall
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism; D010582:Bacteriophage lambda / Q000201:enzymology; D020650:Combinatorial Chemistry Techniques; D004260:DNA Repair / Q000187:drug effects; D045566:DNA, Cruciform / Q000187:drug effects*; D019426:Integrases; D009574:Nitro Compounds / Q000737:chemistry* / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D011437:Propylamines / Q000737:chemistry* / Q000494:pharmacology; D011995:Recombination, Genetic / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D045566:DNA, Cruciform; D009574:Nitro Compounds; D010455:Peptides; D011437:Propylamines; D054852:Small Molecule Libraries; D019426:Integrases