Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 224, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113699
Keywords
Sulfonimidamide; Antibacterial; Bacterial type I Signal peptidase; LepB; Oligopeptides; Serine-lysine protease; Bioisosteres
Categories
Funding
- Swedish Research Council [521-2014-6711, 2017-03953]
- Swedish Research Council [2017-03953] Funding Source: Swedish Research Council
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The incorporation of sulfonimidamide into antibacterial oligopeptides was shown to increase antibacterial activity while reducing cytotoxicity, providing a novel approach for developing new antibiotics.
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. (C) 2021 The Authors. Published by Elsevier Masson SAS.
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