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Fucosylated mixed-chirality linear peptide FHP31 bound to the fucose binding lectin LecB PA-IIL from Pseudomonas aeruginosa at 1.2 Angstrom resolution.Fucosylated mixed-chirality linear peptide FHP31 bound to the fucose binding lectin LecB PA-IIL from Pseudomonas aeruginosa at 1.2 Angstrom resolution.
Structural highlights
FunctionPublication Abstract from PubMedMembrane disruptive alpha-helical antimicrobial peptides (AMPs) offer an opportunity to address multidrug resistance; however, most AMPs are toxic and unstable in serum. These limitations can be partly overcome by introducing D-residues, which often confers protease resistance and reduces toxicity without affecting antibacterial activity, presumably due to lowered alpha-helicity. Here, we investigated 31 diastereomers of the alpha-helical AMP KKLLKLLKLLL. Three diastereomers containing two, three, and four D-residues showed increased antibacterial effects, comparable hemolysis, reduced toxicity against HEK293 cells, and excellent serum stability, while another diastereomer with four D-residues additionally displayed lower hemolysis. X-ray crystallography confirmed that high or low alpha-helicity as measured by circular dichroism indicated alpha-helical or disordered structures independently of the number of chirality switched residues. In contrast to previous reports, alpha-helicity across diastereomers correlated with both antibacterial activity and hemolysis and revealed a complex relationship between stereochemistry, activity, and toxicity, highlighting the potential of diastereomers for property optimization. To Fold or Not to Fold: Diastereomeric Optimization of an alpha-Helical Antimicrobial Peptide.,Personne H, Paschoud T, Fulgencio S, Baeriswyl S, Kohler T, van Delden C, Stocker A, Javor S, Reymond JL J Med Chem. 2023 Jun 8;66(11):7570-7583. doi: 10.1021/acs.jmedchem.3c00460. Epub , 2023 May 25. PMID:37227046[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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