Discovery and mechanistic characterization of a structurally-unique membrane active peptide

Shivani Bansal, Wan Chih Su, Madhu Budamagunta, Wenwu Xiao, Yousif Ajena, Ruiwu Liu, John C Voss, Randy Carney, Atul N. Parikh, Kit S. Lam

Research output: Contribution to journalArticle

Abstract

Membrane active peptides (MAPs) have gained wide interest due to their far reaching applications in drug discovery and drug delivery. The search for new MAPs, however, has been largely skewed with bias selecting for physicochemical parameters believed to be important for membrane activity, such as alpha helicity, cationicity and hydrophobicity. Here we carry out a search-and-find strategy to screen a 100,000-membered one-bead-one-compound (OBOC) combinatorial peptide library for lead compounds, agnostic of those physicochemical constraints. Such a synthetic strategy also permits expansion of our peptide repertoire to include unnatural amino acids. Using this approach, we discovered a structurally unique lead peptide LBF14, a linear 14-mer peptide, that induces gross morphological disruption of membranes, irrespective of membrane composition. Further, we demonstrate that the unique insertion mechanism of the peptide, visualized by spinning disc confocal microscopy and further analyzed by electron paramagnetic resonance measurements, may be the cause of this large scale membrane deformation. We also demonstrate the robustness, reproducibility, and potential application of this technique to discover and characterize new membrane active peptides that display activity by local insertion and subsequent allosteric effects leading to global membrane disruption.

Original languageEnglish (US)
Article number183394
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1862
Issue number10
DOIs
StatePublished - Oct 1 2020

Keywords

  • Combinatorial library
  • Giant unilamellar vesicles
  • Interfacial activity
  • Membrane active peptide
  • Membrane activity
  • Membrane dynamics

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

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