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Scientific article
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English

An intrinsically disordered antimicrobial peptide dendrimer from stereorandomized virtual screening

Published inCell reports physical science, vol. 3, no. 12, 101161
Publication date2022-12-21
First online date2022-12-21
Abstract

Membrane-disruptive amphiphilic antimicrobial peptides behave as intrinsically disordered proteins by being unordered in water and becoming α-helical in contact with biological membranes. We recently discovered that synthesizing the α-helical antimicrobial peptide dendrimer L-T25 ((KL)8(KKL)4(KLL)2 KKLL) using racemic amino acids to form stereorandomized sr-T25, an analytically pure mixture of all possible diastereoisomers of L-T25, preserved antibacterial activity but abolished hemolysis and cytotoxicity, pointing to an intrinsically disordered antibacterial conformation and an α-helical cytotoxic conformation. In this study, to identify non-toxic intrinsically disordered homochiral antimicrobial peptide dendrimers (AMPDs), we surveyed sixty-three sr-analogs of sr-T25 selected by virtual screening. One of the analogs, sr-X18 ((KL)8(KLK)4(KLL)2 KLLL), lost antibacterial activity as L-enantiomer and became hemolytic due to α-helical folding. By contrast, the L- and D-enantiomers of sr-X22 ((KL)8(KL)4(KKLL)2 KLKK) were equally antibacterial, non-hemolytic, and non-toxic, implying an intrinsically disordered bioactive conformation. Screening stereorandomized libraries may be generally useful to identify or optimize intrinsically disordered bioactive peptides.

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Keywords
  • Antimicrobial peptides
  • Dendrimers
  • Intrinsically disordered proteins
  • Membrane disruption
  • Multi-drug resistant bacteria
  • Multidrug resistance
  • Solid-phase peptide synthesis
  • Stereorandomization
  • Virtual screening
Funding
Citation (ISO format)
CAI, Xingguang et al. An intrinsically disordered antimicrobial peptide dendrimer from stereorandomized virtual screening. In: Cell reports physical science, 2022, vol. 3, n° 12, p. 101161. doi: 10.1016/j.xcrp.2022.101161
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Appendix - Article plus supplemental information.
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ISSN of the journal2666-3864
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