Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 231, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114148
Keywords
Competitive CsrA inhibition; Peptides; Phage display; Triazole bridge; Disulfide bridges; Disulfide mimetics
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) through RESIST -Resolving Infection Susceptibility cluster of excellence [EXC 2155]
- Australian Research Council [CE200100012]
- Australian Research Council [CE200100012] Funding Source: Australian Research Council
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Small macrocyclic peptides have potential as new anti-infective drugs, with cyclisation being essential for their activity. Designed disulfide mimetics and a triazole analogue showed activity against different bacterial targets, providing a starting point for medicinal chemistry optimization.
Small macrocyclic peptides are promising candidates for new anti-infective drugs. To date, such peptides have been poorly studied in the context of anti-virulence targets. Using phage display and a self-designed peptide library, we identified a cyclic heptapeptide that can bind the carbon storage regulator A (CsrA) from Yersinia pseudotuberculosis and displace bound RNA. This disulfide-bridged peptide, showed an IC50 value in the low micromolar range. Upon further characterization, cyclisation was found to be essential for its activity. To increase metabolic stability, a series of disulfide mimetics were designed and a redox-stable 1,4-disubstituted 1,2,3-triazole analogue displayed activity in the double-digit micromolar range. Further experiments revealed that this triazole peptidomimetic is also active against CsrA from Escherichia coli and RsmA from Pseudomonas aeruginosa. This study provides an ideal starting point for medicinal chemistry optimization of this macrocyclic peptide and might pave the way towards broad acting virulence modulators.(c) 2022 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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