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

Authors:
Publisher website
Google Scholar
Abstract
Host defence peptides have drawn significant attention as new drugs or drug adjuvants to combat multi-drug resistant bacteria. In this study, we report the development of cyclic derivatives of the immunomodulatory and anti-biofilm innate defence 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.
Funding Information
  • Canadian Institutes of Health Research (FDN154287)
  • Killam Trusts
  • Canada Research Chairs
  • Cystic Fibrosis Foundation
  • Natural Sciences and Engineering Research Council of Canada
  • Michael Smith Health Research BC

This publication has 46 references indexed in Scilit: