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Angew Chem Int Ed Engl. 2018 Jun 25;57(26):7729-7733. doi: 10.1002/anie.201801845. Epub 2018 May 23.

Functionalized Proline-Rich Peptides Bind the Bacterial Second Messenger c-di-GMP.

Author information

1
Laboratorium für Organische Chemie, D-CHAB, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
2
Discovery Chemistry, PRCB, F. Hoffmann-La Roche AG, Grenzacherstr. 124, 4070, Basel, Switzerland.
3
Biozentrum, University of Basel, Klingelbergstr, 50/70, 4056, Basel, Switzerland.

Abstract

c-di-GMP is an attractive target in the fight against bacterial infections since it is a near ubiquitous second messenger that regulates important cellular processes of pathogens, including biofilm formation and virulence. Screening of a combinatorial peptide library enabled the identification of the proline-rich tetrapeptide Gup-Gup-Nap-Arg, which binds c-di-GMP selectively over other nucleotides in water. Computational and CD spectroscopic studies provided a possible binding mode of the complex and enabled the design of a pentapeptide with even higher binding strength towards c-di-GMP. Biological studies showed that the tetrapeptide inhibits biofilm growth by the opportunistic pathogen P. aeruginosa.

KEYWORDS:

antimicrobial compounds; biofilms; c-di-GMP; inhibitors; peptides

PMID:
29521445
DOI:
10.1002/anie.201801845

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