Systematic All-Hydrocarbon Stapling Analysis for Cecropin A Generates a Potent and Stable Antimicrobial Peptide DOI
Yejiao Shi, Gan Luo,

Borui Zhen

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

As an evolutionarily conserved family of antimicrobial peptides (AMPs), cecropins play important role in innate immunity. But their inevitable weaknesses, including poor proteolytic stability and unpredictable cytotoxicity, severely hindered clinical applications. Considering two-helical structure, all-hydrocarbon stapling was performed on cecropin A, successfully generating 27 (i, i + 4) stapled derivatives. By evaluating hemolytic activities, CEC-2–9 with the C-terminus threonine lysine being identified as optimal one. It exerted significantly enhanced antibacterial potency more severe bacterial membrane damage capacity. Compared to its increased helicity hydrophobicity well decreased net charge also enabled improved biocompatibility, facilitating anti-inflammatory efficacy for effective treatment mice peritonitis sepsis. These results have proven that systematic AMPs a feasible approach future development therapeutics.

Language: Английский

Peptide Double-Stapling and Arginine N-Glycosylation Triggered the Development of Therapeutic Antimicrobial Peptides Capable of Killing Drug-Resistant Bacteria in Mice DOI
Xiang Li,

Yanjiao Ding,

Jingwen Xue

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Antimicrobial peptides SAAP-148 exhibited excellent antimicrobial activities but suffered from inherent disadvantages, including cytotoxicity and poor proteolytic stability. Herein, we developed a novel strategy combining one unique silver-catalyzed solid-phase glycosylation-enabled arginine N-glycosylation all-hydrocarbon peptide double-stapling, five-round libraries were rationally constructed containing over 50 stapled and/or N-glycosylated peptides. SLP-51 consisting of two introduced staples the C-terminal glycosylation superior in vitro against drug-resistant Gram-positive or -negative clinical isolates. also improved stability than parent SLP-0, importantly, significantly weakened hemolysis. Experimental modeling mechanism research indicated that exerted similar stronger killing abilities by destroying integrality bacterial membranes. In both skin wound pneumonia models, showcased potent therapeutic effect treating MRSA Klebsiella pneumoniae infection vivo dramatical improvement inflammatory injury.

Language: Английский

Citations

0
Systematic All-Hydrocarbon Stapling Analysis for Cecropin A Generates a Potent and Stable Antimicrobial Peptide DOI
Yejiao Shi, Gan Luo,

Borui Zhen

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

As an evolutionarily conserved family of antimicrobial peptides (AMPs), cecropins play important role in innate immunity. But their inevitable weaknesses, including poor proteolytic stability and unpredictable cytotoxicity, severely hindered clinical applications. Considering two-helical structure, all-hydrocarbon stapling was performed on cecropin A, successfully generating 27 (i, i + 4) stapled derivatives. By evaluating hemolytic activities, CEC-2–9 with the C-terminus threonine lysine being identified as optimal one. It exerted significantly enhanced antibacterial potency more severe bacterial membrane damage capacity. Compared to its increased helicity hydrophobicity well decreased net charge also enabled improved biocompatibility, facilitating anti-inflammatory efficacy for effective treatment mice peritonitis sepsis. These results have proven that systematic AMPs a feasible approach future development therapeutics.

Language: Английский

Citations

0