Cyclic Derivative of Host-Defense Peptide IDR-1018 Improves Proteolytic Stability, Suppresses Inflammation, and Enhances In Vivo Activity

Hashem Etayash, Daniel Pletzer, Prashant Kumar, Suzana K. Straus, Robert E.W. Hancock

Research output: Contribution to journalArticle

Abstract

Host-defense peptides have drawn significant attention as new drugs or drug adjuvants to combat multidrug-resistant bacteria. In this study, we report the development of cyclic derivatives of the immunomodulatory and antibiofilm innate defense regulator peptide (IDR)-1018 based on three different synthetic strategies including head-to-tail cyclization (C1), side-chain-to-tail cyclization (C2), and a disulfide bond cross-linkage (C3). The generated mimetics showed enhanced proteolytic stability and reduced aggregation in vitro and in vivo. The C2 derivative exhibited exceptional ability to suppress inflammation and significantly reduce bacterial loads in a high-density Staphylococcus aureus murine skin infection model. The findings describe different routes to the creation of enzymatically stable mimetics of IDR-1018 and identify a promising new cyclic analogue against bacterial infections.

Original languageEnglish
Pages (from-to)9228-9236
Number of pages9
JournalJournal of medicinal chemistry
Volume63
Issue number17
DOIs
Publication statusPublished - 10 Sep 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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