TY - JOUR
T1 - Functional characterisation and modification of a novel Kunitzin peptide for use as an anti-trypsin antimicrobial peptide against drug-resistant Escherichia coli
AU - Wang, Zhizhong
AU - Ding, Wenjing
AU - Shi, Daning
AU - Chen, Xiaoling
AU - Ma, Chengbang
AU - Jiang, Yangyang
AU - Wang, Tao
AU - Chen, Tianbao
AU - Shaw, Chris
AU - Wang, Lei
AU - Zhou, Mei
PY - 2024/11
Y1 - 2024/11
N2 - In recent decades, antimicrobial peptides (AMPs) have emerged as highly promising candidates for the next generation of antibiotic agents, garnering significant attention. Although their potent antimicrobial activities and ability to combat drug resistance make them stand out among alternative agents, their poor stability has presented a great challenge for further development. In this work, we report a novel Kunitzin AMP, Kunitzin-OL, from the frog Odorrana lividia, exhibiting dual antimicrobial and anti-trypsin activities. Through functional screening and comparison with previously reported Kunitzin peptides, we serendipitously discovered a unique motif (-KVKF-) and unveiled its crucial role in the antibacterial functions of Kunitzin-OL by modifying it through motif removal and duplication. Among the designed derivatives, peptides 4 and 8 demonstrated remarkable antimicrobial activities and low cytotoxicity, with high therapeutic index (TI) values (TI = 20.8, TI = 20.8). Furthermore, they showed potent antibacterial efficacy against drug-resistant Escherichia coli strains and exhibited lipopolysaccharide (LPS)-neutralising activity, effectively alleviating LPS-induced inflammatory responses. Overall, our findings provide a new short motif for designing effective AMP drugs and highlight the potential of the Kunitztin trypsin inhibitory loop as a valuable motif for the design of AMPs with enhancing proteolytic stability.
AB - In recent decades, antimicrobial peptides (AMPs) have emerged as highly promising candidates for the next generation of antibiotic agents, garnering significant attention. Although their potent antimicrobial activities and ability to combat drug resistance make them stand out among alternative agents, their poor stability has presented a great challenge for further development. In this work, we report a novel Kunitzin AMP, Kunitzin-OL, from the frog Odorrana lividia, exhibiting dual antimicrobial and anti-trypsin activities. Through functional screening and comparison with previously reported Kunitzin peptides, we serendipitously discovered a unique motif (-KVKF-) and unveiled its crucial role in the antibacterial functions of Kunitzin-OL by modifying it through motif removal and duplication. Among the designed derivatives, peptides 4 and 8 demonstrated remarkable antimicrobial activities and low cytotoxicity, with high therapeutic index (TI) values (TI = 20.8, TI = 20.8). Furthermore, they showed potent antibacterial efficacy against drug-resistant Escherichia coli strains and exhibited lipopolysaccharide (LPS)-neutralising activity, effectively alleviating LPS-induced inflammatory responses. Overall, our findings provide a new short motif for designing effective AMP drugs and highlight the potential of the Kunitztin trypsin inhibitory loop as a valuable motif for the design of AMPs with enhancing proteolytic stability.
KW - Drug resistance
KW - Proteolytic tolerance
KW - Anti-endotoxin
KW - Antimicrobial peptides
KW - Peptide modification
U2 - 10.1016/j.bcp.2024.116508
DO - 10.1016/j.bcp.2024.116508
M3 - Article
C2 - 39186954
SN - 1873-2968
VL - 229
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
M1 - 116508
ER -