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Antibacterial sulfonimidamide-based oligopeptides as type I signal peptidase inhibitors: Synthesis and biological evaluation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery. Uppsala University.ORCID iD: 0000-0002-6378-5808
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
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2021 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 224, article id 113699Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2021. Vol. 224, article id 113699
Keywords [en]
Antibacterial, Bacterial type I Signal peptidase, Bioisosteres, LepB, Oligopeptides, Serine-lysine protease, Sulfonimidamide
National Category
Medicinal Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-450022DOI: 10.1016/j.ejmech.2021.113699ISI: 000703110000028PubMedID: 34352713OAI: oai:DiVA.org:uu-450022DiVA, id: diva2:1583780
Funder
Swedish Research Council, 521-2014-671Swedish Research Council, 2017–03953Available from: 2021-08-09 Created: 2021-08-09 Last updated: 2024-04-01Bibliographically approved
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Benediktsdottir, AndreaLu, LuCao, ShaZamaratski, EdouardKarlén, AndersMowbray, Sherry LHughes, DiarmaidSandström, Anja

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Benediktsdottir, AndreaLu, LuCao, ShaZamaratski, EdouardKarlén, AndersMowbray, Sherry LHughes, DiarmaidSandström, Anja
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Drug Design and DiscoveryStructural BiologyDepartment of Medical Biochemistry and MicrobiologyDepartment of Medicinal ChemistryDepartment of Cell and Molecular BiologyScience for Life Laboratory, SciLifeLab
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