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An intrinsically disordered antimicrobial peptide dendrimer from stereorandomized virtual screening
Xingguang Cai1, Markus Orsi1, Alice Capecchi1
1Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland.
Cell Reports. Physical Science
|January 12, 2023
Summary
Stereorandomized antimicrobial peptide dendrimers offer a strategy to develop non-toxic antibacterial agents. This approach identified intrinsically disordered peptide conformations that are antibacterial but not hemolytic or cytotoxic.
Area of Science:
- Biochemistry
- Materials Science
- Medicinal Chemistry
Background:
- Amphiphilic antimicrobial peptides (AMPs) are intrinsically disordered in solution but adopt alpha-helical structures upon membrane interaction.
- Previous work demonstrated that stereorandomization of an alpha-helical AMP dendrimer (L-T25) yielded a mixture (sr-T25) with preserved antibacterial activity but abolished hemolysis and cytotoxicity.
- This suggests distinct conformations for antibacterial and cytotoxic activities.
Purpose of the Study:
- To identify non-toxic, intrinsically disordered, homochiral antimicrobial peptide dendrimers (AMPDs).
- To explore the utility of screening stereorandomized libraries for optimizing bioactive peptides.
Main Methods:
- Virtual screening of sixty-three stereorandomized analogs of sr-T25.
- Synthesis and characterization of selected analogs.
- Evaluation of antibacterial activity, hemolysis, and cytotoxicity.
Main Results:
- One analog, sr-X18, lost antibacterial activity and became hemolytic in its L-enantiomer due to alpha-helical folding.
- In contrast, both L- and D-enantiomers of sr-X22 were equally antibacterial, non-hemolytic, and non-toxic.
- sr-X22's properties suggest an intrinsically disordered bioactive conformation.
Conclusions:
- Stereorandomized libraries are effective for identifying or optimizing intrinsically disordered bioactive peptides.
- This strategy can yield potent antibacterial agents with reduced toxicity.
- The findings highlight the importance of molecular conformation in determining AMP activity and safety profiles.
