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Updated: Jun 11, 2026

Production and Testing of Antimicrobial Peptides and Their Mimics
Published on: April 10, 2026
All-Hydrocarbon Stapling and Amino Acid Substitution-Modified Antimicrobial Peptide Feleucin-K3 Analogs Enhanced the
Bei Gao1,2, Yue Jia1, Tiantian Yan1
1Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China.
Abstract:
Our previous research found that the poor stability of the antimicrobial peptide Feleucin-K3 (FK3) had limited its transition into clinical application. Herein, we developed a series of FK3 derivatives stapled by all-hydrocarbon and thioether to enhance the stability and then implemented an amino acid substitution strategy to reduce the hemolytic toxicity. Consequently, after replacing the first phenylalanine of FK3 with alanine and conducting (i, i + 4) all-hydrocarbon stapling with (S)-2-(4-pentenyl) alanine at the 5,9-position, analog S1-1A displayed the highest therapeutic index, high stability, and potent antimicrobial effects against multidrug-resistant (MDR) bacteria as well as antibiofilm properties. A striking finding was that S1-1A exhibited 8-fold greater antimicrobial activity against resistant strains of Staphylococcus aureus than vancomycin. The efficacy of S1-1A in vivo was as effective as vancomycin in the skin wound infection model. Overall, stapled peptide S1-1A showed promising potential for being developed into a novel drug for combating MDR bacterial infections.
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