TY - JOUR
T1 - C-terminal modification of a de novo designed antimicrobial peptide via capping of macrolactam rings
AU - Zeng, Ping
AU - Cheng, Qipeng
AU - Yi, Lanhua
AU - Shui Yee Leung, Sharon
AU - Chen, Sheng
AU - Chan, Kin Fai
AU - Wong, Kwok Yin
N1 - Funding Information:
We thank Dr. Chin-fung Chan for the provision of fresh rat blood. We also thank the University Research Facilities in Life Sciences (ULS), Materials Characterization and Device Fabrication (UMF) of The Hong Kong Polytechnic University; Department of Physics, The Chinese University of Hong Kong for providing facilities for biological and SEM studies. We acknowledge support from the Research Grants Council of Hong Kong (grant no. C5026-16G), the Innovation and Technology Commission, and The Hong Kong Polytechnic University.
Funding Information:
We thank Dr. Chin-fung Chan for the provision of fresh rat blood. We also thank the University Research Facilities in Life Sciences (ULS), Materials Characterization and Device Fabrication (UMF) of The Hong Kong Polytechnic University; Department of Physics, The Chinese University of Hong Kong for providing facilities for biological and SEM studies. We acknowledge support from the Research Grants Council of Hong Kong (grant no. C5026-16G), the Innovation and Technology Commission, and The Hong Kong Polytechnic University.
Publisher Copyright:
© 2022
PY - 2023/1
Y1 - 2023/1
N2 - In this work, by capping a macrolactam ring at the C-terminus of a de novo-designed peptide, namely zp80, we have constructed a small peptide library via the solid phase peptide synthesis for screening. Eight peptides bearing different aspartic acid-rich macrolactam rings but the same linear (IIRR)4 unit exhibited improved antibacterial activities, hemolytic activity, and selectivity index. Mechanistic studies revealed that they could destroy the integrity of bacterial envelope, leading to cytoplasm leakage and rapid dissipation of membrane potential. One of these peptides, zp90 with a macrolactam ring of (KaDGD), demonstrated preferential interaction with calcium ions at a stoichiometric ratio of 1:1, promoting the affinity of designed peptides to bacterial membrane. Overall, this work provides a feasible strategy for medicinal chemists to further develop potent, selective, and multifunctional de novo-designed antimicrobial peptides.
AB - In this work, by capping a macrolactam ring at the C-terminus of a de novo-designed peptide, namely zp80, we have constructed a small peptide library via the solid phase peptide synthesis for screening. Eight peptides bearing different aspartic acid-rich macrolactam rings but the same linear (IIRR)4 unit exhibited improved antibacterial activities, hemolytic activity, and selectivity index. Mechanistic studies revealed that they could destroy the integrity of bacterial envelope, leading to cytoplasm leakage and rapid dissipation of membrane potential. One of these peptides, zp90 with a macrolactam ring of (KaDGD), demonstrated preferential interaction with calcium ions at a stoichiometric ratio of 1:1, promoting the affinity of designed peptides to bacterial membrane. Overall, this work provides a feasible strategy for medicinal chemists to further develop potent, selective, and multifunctional de novo-designed antimicrobial peptides.
KW - Antimicrobial peptide
KW - Calcium ion-binding affinity
KW - Macrolactam ring
KW - Membrane potential
KW - Selectivity index
UR - http://www.scopus.com/inward/record.url?scp=85141445499&partnerID=8YFLogxK
U2 - 10.1016/j.bioorg.2022.106251
DO - 10.1016/j.bioorg.2022.106251
M3 - Journal article
C2 - 36370649
AN - SCOPUS:85141445499
SN - 0045-2068
VL - 130
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 106251
ER -