Small molecule functional analogs of peptides that inhibit lambda site-specific recombination and bind Holliday junctions.
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.
Ranjit
Dev K
DK
Department of Biology and Center for Microbial Sciences, San Diego State University, San Diego, CA 92182-4614, USA.
Rideout
Marc C
MC
Nefzi
Adel
A
Ostresh
John M
JM
Pinilla
Clemencia
C
Segall
Anca M
AM
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
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D045566:DNA, Cruciform; D009574:Nitro Compounds; D010455:Peptides; D011437:Propylamines; D054852:Small Molecule Libraries; D019426:Integrases