Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB)

Maria De Rosa; Lu Lu; Edouard Zamaratski; Natalia Szałaj; Sha Cao; Henrik Wadensten; Lena Lenhammar; Johan Gising; Annette K Roos; Douglas L Huseby; Rolf Larsson; Per E Andrén; Diarmaid Hughes; Peter Brandt; Sherry L Mowbray; Anders Karlén

doi:10.1016/j.bmc.2016.12.003

Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB)

Bioorg Med Chem. 2017 Feb 1;25(3):897-911. doi: 10.1016/j.bmc.2016.12.003. Epub 2016 Dec 7.

Authors

Affiliations

¹ Uppsala University, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Box 574, SE-751 23 Uppsala, Sweden.
² Uppsala University, Department of Cell and Molecular Biology, BMC, Box 596, SE-751 24 Uppsala, Sweden.
³ Uppsala University, Department of Medical Biochemistry and Microbiology, BMC, Box 582, SE-751 23 Uppsala, Sweden.
⁴ Uppsala University, Department of Pharmaceutical Biosciences, BMC, Box 591, SE-751 24 Uppsala, Sweden.
⁵ Uppsala University Hospital, Department of Medical Sciences, Uppsala, Sweden.
⁶ Uppsala University, Science for Life Laboratory, Department of Cell and Molecular Biology, BMC, Box 596, SE-751 24 Uppsala, Sweden.
⁷ Uppsala University, Department of Cell and Molecular Biology, BMC, Box 596, SE-751 24 Uppsala, Sweden; Uppsala University, Science for Life Laboratory, Department of Cell and Molecular Biology, BMC, Box 596, SE-751 24 Uppsala, Sweden. Electronic address: Sherry.Mowbray@icm.uu.se.
⁸ Uppsala University, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Box 574, SE-751 23 Uppsala, Sweden. Electronic address: Anders.Karlen@orgfarm.uu.se.

PMID: 28038943
DOI: 10.1016/j.bmc.2016.12.003

Abstract

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.

Keywords: Antibacterials; Escherichia coli; Oligopeptides; Solid-phase peptide synthesis; Type I signal peptidase.

MeSH terms

Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Escherichia coli / enzymology*
Hep G2 Cells
Humans
Membrane Proteins / antagonists & inhibitors*
Membrane Proteins / metabolism
Models, Molecular
Molecular Structure
Oligopeptides / chemical synthesis
Oligopeptides / chemistry
Oligopeptides / pharmacology*
Serine Endopeptidases / metabolism
Structure-Activity Relationship

Substances

Membrane Proteins
Oligopeptides
Serine Endopeptidases
type I signal peptidase