wrwyrggrywrw is a single-chain functional analog of the Holliday junction-binding homodimer, (wrwycr)2 |
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| Affiliation: | 1. Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA;2. Laboratory of Molecular Pharmacology, CCR, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;1. Laboratory of Analytical Chemistry, Department of Chemistry, Athens University, Athens 15771, Greece;2. Laboratory of Medical Genetics, Athens University, Athens 11527, Greece;3. Department of Chemistry, University of Patras, Patras 26500, Greece;4. Foundation for Research and Technology Hellas, Institute of Chemical Engineering and High Temperature Chemical Processes (FORTH/ICE-HT), Patras 26504, Greece;1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School Sichuan University, China;2. West China Medical School, West China Hospital, Sichuan University, China;3. Cancer Center, West China Hospital, Sichuan University, China |
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| Abstract: | DNA repair pathways in bacteria that use homologous recombination involve the formation and subsequent resolution of Holliday junction (HJ) intermediates. We have previously identified several hexameric peptides that bind to HJs and interfere with HJ processing enzymes in vitro. The peptide WRWYCR and its D-amino acid stereoisomer wrwycr, are potent antibacterial agents. These hexapeptides must form homodimers in order to interact stably with HJs, and inhibit bacterial growth, and this represents a potential limitation. Herein we describe a disulfide bond-independent inhibitor, WRWYRGGRYWRW and its D-stereoisomer wrwyrggrywrw. We have characterized these single-chain, linear analogs of the hexapeptides, and show that in addition to effectively binding to HJs, and inhibiting the activity of DNA repair enzymes that process HJs, they have equal or greater potency against Gram-positive and Gram-negative bacterial growth. The analogs were also shown to cause DNA damage in bacteria, and disrupt the integrity of the bacterial cytoplasmic membrane. Finally, we found that they have little toxicity toward several eukaryotic cell types at concentrations needed to inhibit bacterial growth. |
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