title: Semi-synthesis of biologically active nisin hybrids composed of the native lanthionine ABC-fragment and a cross-stapled synthetic DE-fragment.
abstract: The antimicrobial peptide nisin is a promising template for designing novel peptide-based antibiotics to improve its drug-like properties. First steps in that direction represent the synthesis of hybrid nisin derivatives that contain a native nisin ABC-part and synthesized cross-stapled DE-ring fragments and are described here. The biological activity of the newly synthesized nisin derivatives was evaluated in order to compare the bioactivity of the synthetic DE-ring containing mimic and native lanthionine-bridged DE-ring containing nisin. The native nisin ABC-ring system was obtained via chymotrypsin digestion of full-length nisin, and was subsequently functionalized at the C-terminal carboxylate with two different amino alkyne moieties. Next, nisin hybrids were successfully prepared using Cu(I)-catalyzed azide alkyne cycloaddition 'click' chemistry by chemo-selective ligation of the ABC-alkyne with the N-terminal azido functionalized dicarba-DE ring mimic. The newly synthesized compounds were active as potent lipid II binders and retained antimicrobial activity in a growth inhibition assay. However, pore formation was not observed, possibly either due to the different character of the 'staples' as compared to the parent sulfides, or due to the triazole moiety as a sub-optimal amide bond isostere.
authors.affiliation: Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: Jack C
authors.initials: JC
authors.lastname: Slootweg
authors.affiliation: Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: Nienke
authors.initials: N
authors.lastname: Peters
authors.affiliation: Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: H Linda C
authors.initials: HL
authors.lastname: Quarles van Ufford
authors.affiliation: Membrane Biochemistry & Biophysics, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: Eefjan
authors.initials: E
authors.lastname: Breukink
authors.affiliation: Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands; Chemical Biology and Medicinal Chemistry, School of Chemistry, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
authors.affiliation: Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands. Electronic address: D.T.S.Rijkers@uu.nl.
authors.forename: Dirk T S
authors.initials: DT
authors.lastname: Rijkers
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects* / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D009561:Nisin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D013440:Sulfides; D009561:Nisin; C001520:lanthionine; D000409:Alanine
keywords: Antimicrobial peptides; Cu(I)-catalyzed click chemistry; Lantibiotics; Membrane interactions; Nisin; Peptide pharmaceuticals; Semi-synthesis