Semi-synthesis of biologically active nisin hybrids composed of the native lanthionine ABC-fragment and a cross-stapled synthetic DE-fragment |
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| Affiliation: | 1. 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;2. Membrane Biochemistry & Biophysics, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands;3. Chemical Biology and Medicinal Chemistry, School of Chemistry, University of Glasgow, Glasgow G12 8QQ, United Kingdom;1. Hubei Collaboration Innovation Center of Non-power Nuclear Technology, Hubei University of Science and Technology, Xianning 437100, China;2. College of Chemical Engineering, Wuhan University of Technology, Wuhan 430070, China;3. School of Nuclear Technology & Chemistry and Biology, Hubei University of Science and Technology, Xianning 437100, China;1. Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;1. Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad, 2001, Colonia Chamilpa, Apartado Postal 510-3, Cuernavaca 62210, Mexico;2. Illawarra Health and Medical Research Institute, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia |
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| 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. |
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| Keywords: | Antimicrobial peptides Cu(I)-catalyzed click chemistry Lantibiotics Membrane interactions Nisin Peptide pharmaceuticals Semi-synthesis |
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