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Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2017 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 25, no 3, p. 897-911Article in journal (Refereed) Published
Abstract [en]

Type I signal peptidases are potential targets for the development of new antibacterial agents. Here we report finding potent inhibitors of E. coli type I signal peptidase (LepB), by optimizing a previously reported hit compound, decanoyl-PTANA-CHO, through modifications at the N- and C-termini. Good improvements of inhibitory potency were obtained, with IC50s in the low nanomolar range. The best inhibitors also showed good antimicrobial activity, with MICs in the low μg/mL range for several bacterial species. The selection of resistant mutants provided strong support for LepB as the target of these compounds. The cytotoxicity and hemolytic profiles of these compounds are not optimal but the finding that minor structural changes cause the large effects on these properties suggests that there is potential for optimization in future studies.

Place, publisher, year, edition, pages
2017. Vol. 25, no 3, p. 897-911
Keyword [en]
Antibacterials, Escherichia coli, Oligopeptides, Solid-phase peptide synthesis, Type I signal peptidase
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-314110DOI: 10.1016/j.bmc.2016.12.003ISI: 000394201900009PubMedID: 28038943OAI: oai:DiVA.org:uu-314110DiVA, id: diva2:1069260
Funder
Swedish Research Council, 521-2014-6711 521-2013-2904 521-2013-3105 621-2014-6215Swedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

Maria De Rosa and Lu Lu contributed equally to this work.

Available from: 2017-01-27 Created: 2017-01-27 Last updated: 2018-01-13Bibliographically approved

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De Rosa, MariaLu, LuZamaratski, EdouardCao, ShaWadensten, HenrikLenhammar, LenaGising, JohanRoos, Annette K.Huseby, Douglas LLarsson, RolfAndrén, Per E.Hughes, DiarmaidBrandt, PeterMowbray, Sherry L.Karlen, Anders
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Organic Pharmaceutical ChemistryScience for Life Laboratory, SciLifeLabStructure and Molecular BiologyDepartment of Medicinal ChemistryDepartment of Medical Biochemistry and MicrobiologyDepartment of Pharmaceutical BiosciencesCancer Pharmacology and Computational MedicineDepartment of Medical SciencesDepartment of Cell and Molecular Biology
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