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Discovery and mechanistic characterization of a structurally-unique membrane active peptide
Shivani Bansal1, Wan-Chih Su2, Madhu Budamagunta3
1Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, United States of America; Department of Chemistry, University of California, Davis, United States of America.
Biochimica Et Biophysica Acta. Biomembranes
|June 21, 2020
Summary
Researchers discovered a new peptide, LBF14, that disrupts cell membranes through a unique insertion mechanism. This finding offers a novel approach for discovering membrane active peptides (MAPs) for drug discovery and delivery.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Membrane active peptides (MAPs) are crucial for drug discovery and delivery.
- Traditional MAP discovery is biased by specific physicochemical properties.
- A need exists for unbiased methods to identify novel MAPs.
Purpose of the Study:
- To develop an unbiased strategy for discovering novel membrane active peptides (MAPs).
- To identify lead compounds from a large combinatorial library, irrespective of traditional parameters.
- To characterize the mechanism of action of newly discovered MAPs.
Main Methods:
- Screening of a 100,000-membered one-bead-one-compound (OBOC) combinatorial peptide library.
- Utilizing a search-and-find strategy agnostic to conventional physicochemical constraints.
- Employing spinning disc confocal microscopy and electron paramagnetic resonance (EPR) for mechanism analysis.
Main Results:
- Discovery of a structurally unique linear 14-mer peptide, LBF14.
- LBF14 induces significant morphological disruption of membranes, independent of membrane composition.
- Visualization of a unique peptide insertion mechanism responsible for membrane deformation.
Conclusions:
- The developed strategy successfully identified a novel MAP with a unique mechanism of action.
- LBF14's insertion mechanism leads to allosteric effects and global membrane disruption.
- This technique is robust and reproducible for discovering and characterizing new MAPs.
