Personne, Hippolyte; Paschoud, Thierry; Fulgencio, Sofia; Baeriswyl, Stéphane; Köhler, Thilo; van Delden, Christian; Stocker, Achim; Javor, Sacha; Reymond, Jean-Louis (2023). To Fold or Not to Fold: Diastereomeric Optimization of an α-Helical Antimicrobial Peptide. Journal of medicinal chemistry, 66(11), pp. 7570-7583. American Chemical Society 10.1021/acs.jmedchem.3c00460
|
Text
acs.jmedchem.3c00460.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (4MB) | Preview |
Membrane disruptive α-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 α-helicity. Here, we investigated 31 diastereomers of the α-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 α-helicity as measured by circular dichroism indicated α-helical or disordered structures independently of the number of chirality switched residues. In contrast to previous reports, α-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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP) |
UniBE Contributor: |
Personne, Hippolyte Jean-Claude René, Paschoud, Thierry, Baeriswyl, Stéphane, Stocker, Achim, Javor, Sacha, Reymond, Jean-Louis |
Subjects: |
500 Science > 570 Life sciences; biology 500 Science > 540 Chemistry |
ISSN: |
0022-2623 |
Publisher: |
American Chemical Society |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
26 May 2023 15:05 |
Last Modified: |
09 Jun 2023 00:16 |
Publisher DOI: |
10.1021/acs.jmedchem.3c00460 |
PubMed ID: |
37227046 |
BORIS DOI: |
10.48350/182936 |
URI: |
https://boris.unibe.ch/id/eprint/182936 |
Actions (login required)
 |
Edit item |