Antibacterial sulfonimidamide-based oligopeptides as type I signal peptidase inhibitors: Synthesis and biological evaluation.

Autor: Benediktsdottir A; Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, SE-75123, Uppsala, Sweden., Lu L; Department of Cell and Molecular Biology, BMC, Uppsala University, Box 596, SE-75123, Uppsala, Sweden., Cao S; Department of Medical Biochemistry and Microbiology, BMC, Box 582, SE-75123, Uppsala, Sweden., Zamaratski E; Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, SE-75123, Uppsala, Sweden., Karlén A; Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, SE-75123, Uppsala, Sweden., Mowbray SL; Department of Cell and Molecular Biology, BMC, Uppsala University, Box 596, SE-75123, Uppsala, Sweden; Uppsala University, Science for Life Laboratory, Department of Cell and Molecular Biology, Box 596, SE-751 24, Uppsala, Sweden., Hughes D; Department of Medical Biochemistry and Microbiology, BMC, Box 582, SE-75123, Uppsala, Sweden., Sandström A; Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, SE-75123, Uppsala, Sweden. Electronic address: anja.sandstrom@ilk.uu.se.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Nov 15; Vol. 224, pp. 113699. Date of Electronic Publication: 2021 Jul 13.
DOI: 10.1016/j.ejmech.2021.113699
Abstrakt: Oligopeptide boronates with a lipophilic tail are known to inhibit the type I signal peptidase in E. coli, which is a promising drug target for developing novel antibiotics. Antibacterial activity depends on these oligopeptides having a cationic modification to increase their permeation. Unfortunately, this modification is associated with cytotoxicity, motivating the need for novel approaches. The sulfonimidamide functionality has recently gained much interest in drug design and discovery, as a means of introducing chirality and an imine-handle, thus allowing for the incorporation of additional substituents. This in turn can tune the chemical and biological properties, which are here explored. We show that introducing the sulfonimidamide between the lipophilic tail and the peptide in a series of signal peptidase inhibitors resulted in antibacterial activity, while the sulfonamide isostere and previously known non-cationic analogs were inactive. Additionally, we show that replacing the sulfonamide with a sulfonimidamide resulted in decreased cytotoxicity, and similar results were seen by adding a cationic sidechain to the sulfonimidamide motif. This is the first report of incorporation of the sulfonimidamide functional group into bioactive peptides, more specifically into antibacterial oligopeptides, and evaluation of its biological effects.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article.
(Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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