Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB). Issue 3 (1st February 2017)

• Record Type: Journal Article
• Authors: De Rosa, Maria; Lu, Lu; Zamaratski, Edouard; Szałaj, Natalia; Cao, Sha; Wadensten, Henrik; Lenhammar, Lena; Gising, Johan; Roos, Annette K.; Huseby, Douglas L.; Larsson, Rolf; Andrén, Per E.; Hughes, Diarmaid; Brandt, Peter; Mowbray, Sherry L.; Karlén, Anders
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 3(2017)
• Page Start: 897
• Page End: 911
• Publication Date: 2017-02-01
• Subjects: dabcyl 4-((4-(dimethylamino)phenyl)azo)benzoic acid -- DCM dichloromethane -- DIEA N, N-diisopropylethylamine -- DMF N, N-dimethylformamide -- E. coli Escherichia coli -- EDANS 5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid -- EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide -- Fmoc 9-fluorenylmethoxycarbonyl -- HBTU N, N, N′, N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate -- HATU 1-[bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxide hexafluorophosphate -- HFIP 1, 1, 1, 3, 3, 3-hexafluoro-2-propanol -- IC50 half maximal inhibitory concentration -- MIC minimal inhibitory concentration -- SPPS solid-phase peptide synthesis -- TES triethylsilane -- SPase I type I signal peptidase -- TFA trifluoroacetic acid; Antibacterials -- Escherichia coli -- Oligopeptides -- Solid-phase peptide synthesis -- Type I signal peptidase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.12.003
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 IC50 s 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.