biostudies-literatureMuhammad TElisabeth and Alfred Ahlqvists stiftelseSwedish Research CouncilElisabeth and Alfred Ahlqvists stiftelse postdoctoral scholarship504https://www.ebi.ac.uk/biostudies/studies/S-EPMC9953701biostudies-literatureUnknown11(2)Is it possible to enhance structural stability and biological activity of KR-12, a truncated antimicrobial peptide derived from the human host defense peptide LL-37? Based on the mapping of essential residues in KR-12, we have designed backbone-cyclized dimers, cross-linked via a disulfide bond to improve peptide stability, while at the same time improving on-target activity. Circular dichroism showed that each of the dimers adopts a primarily alpha-helical conformation (55% helical content) when bound to lyso-phosphatidylglycerol micelles, indicating that the helical propensity of the parent peptide is maintained in the new cross-linked cyclic form. Compared to KR-12, one of the cross-linked dimers showed 16-fold more potent antimicrobial activity against human pathogens <i>Pseudomonas aeBiomedicinesTransforming Cross-Linked Cyclic Dimers of KR-12 into Stable and Potent Antimicrobial Drug Leads.PMC9953701Medicine and Health, #2011-03403; UGPostdoctoral Scholarship: TM#2011-03403Gunasekera SMuhammad TStromstedt AAGoransson UfalseTransforming Cross-Linked Cyclic Dimers of KR-12 into Stable and Potent Antimicrobial Drug Leads.Is it possible to enhance structural stability and biological activity of KR-12, a truncated antimicrobial peptide derived from the human host defense peptide LL-37? Based on the mapping of essential residues in KR-12, we have designed backbone-cyclized dimers, cross-linked via a disulfide bond to improve peptide stability, while at the same time improving on-target activity. Circular dichroism showed that each of the dimers adopts a primarily alpha-helical conformation (55% helical content) when bound to lyso-phosphatidylglycerol micelles, indicating that the helical propensity of the parent peptide is maintained in the new cross-linked cyclic form. Compared to KR-12, one of the cross-linked dimers showed 16-fold more potent antimicrobial activity against human pathogens <i>Pseudomonas ae2023-01-01T00:00:00Z2023 Feb2026-04-08T14:33:04.234Z2025-02-18T23:44:22.418ZS-EPMC99537013683104010.3390/biomedicines11020504