Document Type
Article
Publication Date
12-27-2022
Abstract
A series of small (7–12 mer) amphipathic cationic peptides were designed and synthesized to create short helical peptides with broad-range bactericidal activity and selectivity toward the bacterial cells. The analysis identified a lead 12-mer peptide 8b with broad-spectrum activity against Gram-positive (MIC = 3.1–6.2 μg/mL) and Gram-negative (MIC = 6.2–12.5 μg/mL) bacteria and selectivity toward prokaryotic versus eukaryotic cells (HC50 = 280 μg/mL, >75% cell viability at 150 μg/mL). The rapid membranolytic action of 8b was demonstrated by a calcein dye leakage assay and confirmed using scanning electron microscopy. According to circular dichroism and NMR spectroscopy, the peptides have an irregular spatial structure in water. A lipid bilayer induced an amphipathic helix only in 12-mer peptides, including 8b. Molecular dynamics simulations provided detailed information about the interaction of 8b and its closest analogues with bacterial and mammalian membranes and revealed the roles of particular amino acids in the activity and selectivity of peptides.
Recommended Citation
Lohan, S.; Konshina, A. G.; Efremov, R. G.; Maslennikov, I.; Parang, K. Structure-based rational design of small α-helical peptides with broad-spectrum activity against multidrug-resistant pathogens. J. Med. Chem. 2023, 66, 855-874. https://doi.org/10.1021/acs.jmedchem.2c01708
Copyright
The authors
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Medicinal and Pharmaceutical Chemistry Commons, Other Pharmacy and Pharmaceutical Sciences Commons
Comments
This article was originally published in Journal of Medicinal Chemistry, volume 66, issue 1, in 2023. https://doi.org/10.1021/acs.jmedchem.2c01708