Semi-synthesis of biologically active nisin hybrids composed of the native lanthionine ABC-fragment and a cross-stapled synthetic DE-fragment

Slootweg, J. C., Peters, N., Quarles van Ufford, H. (L.) C., Breukink, E., Liskamp, R. M.J. and Rijkers, D. T.S. (2014) Semi-synthesis of biologically active nisin hybrids composed of the native lanthionine ABC-fragment and a cross-stapled synthetic DE-fragment. Bioorganic and Medicinal Chemistry, 22(19), pp. 5345-5353. (doi:10.1016/j.bmc.2014.07.046) (PMID:25199583)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liskamp, Professor Robert
Authors: Slootweg, J. C., Peters, N., Quarles van Ufford, H. (L.) C., Breukink, E., Liskamp, R. M.J., and Rijkers, D. T.S.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Bioorganic and Medicinal Chemistry
Publisher:Pergamon Press
ISSN:0968-0896
ISSN (Online):1464-3391

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