title: Antimicrobial benzodiazepine-based short cationic peptidomimetics.
abstract: Antimicrobial peptides (AMPs) appear to be good candidates for the development of new antibiotic drugs. We describe here the synthesis of peptidomimetic compounds that are based on a benzodiazepine scaffold flanked with positively charged and hydrophobic amino acids. These compounds mimic the essential properties of cationic AMPs. The new design possesses the benzodiazepine scaffold that is comprised of two glycine amino acids and which confers flexibility and aromatic hydrophobic 'back', and two arms used for further synthesis on solid phase for incorporation of charged and hydrophobic amino acids. This approach allowed us a better understanding of the influence of these features on the antimicrobial activity and selectivity. A novel compound was discovered which has MICs of 12.5 µg/ml against Staphylococcus aureus and 25 µg/ml against Escherichia coli, similar to the well-known antimicrobial peptide MSI-78. In contrast to MSI-78, the above mentioned compound has lower lytic effect against mammalian red blood cells. These peptidomimetic compounds will pave the way for future design of potent synthetic mimics of AMPs for therapeutic and biomedical applications.
authors: Department of Chemistry, Bar-Ilan University, Ramat Gan, 52900, Israel.|Department of Biological Chemistry, Ariel University, Ariel, 40700, Israel.
authors: Galina M
authors: GM
authors: Zats
authors: Department of Chemistry, Bar-Ilan University, Ramat Gan, 52900, Israel.|Department of Biological Chemistry, Ariel University, Ariel, 40700, Israel.
authors: Marina
authors: M
authors: Kovaliov
authors: Department of Chemistry, Bar-Ilan University, Ramat Gan, 52900, Israel.
authors: Amnon
authors: A
authors: Albeck
authors: Department of Biological Chemistry, Ariel University, Ariel, 40700, Israel.
authors: Shimon
authors: S
authors: Shatzmiller
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry*; D002412:Cations / Q000138:chemical synthesis / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides / Q000737:chemistry; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D002412:Cations; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D057786:Peptidomimetics; D001569:Benzodiazepines; C073978:peptide 78
keywords: antimicrobial peptide; benzodiazepine scaffold; cationic peptides; drug design; peptidomimetics