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Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
Spontaneous membrane-translocating peptides by orthogonal high-throughput screening
Jessica R Marks1, Jesse Placone, Kalina Hristova
1Department of Biochemistry, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Journal of the American Chemical Society
|May 7, 2011
Summary
Researchers identified a novel peptide motif that spontaneously crosses cell membranes without damage. This discovery could revolutionize drug delivery by enabling transport of membrane-impermeant molecules into cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Delivery
Background:
- Cell-penetrating peptides (CPPs) are crucial for intracellular delivery.
- Conventional CPPs like HIV tat peptide primarily use endocytosis, limiting their efficiency and cargo capacity.
- Synthetic lipid bilayers present a barrier to many molecules, including potential therapeutics.
Purpose of the Study:
- To identify peptides capable of spontaneous translocation across lipid bilayers without causing membrane permeabilization.
- To characterize the sequence and properties of these novel membrane-translocating peptides.
- To develop chemical tools for rapid identification of such peptides for drug delivery applications.
Main Methods:
- Combinatorial peptide chemistry for library synthesis.
- Orthogonal high-throughput screening for functional peptide selection.
- Utilizing synthetic multibilayer vesicles and cell-based assays to validate translocation.
- Characterizing conserved sequence motifs within identified peptides.
Main Results:
- A conserved 9-residue motif was identified, characterized by cationic residues in a hydrophobic sequence.
- This motif demonstrated rapid spontaneous translocation across synthetic bilayers and into cells.
- The motif successfully carried a large polar dye as a cargo moiety.
- Unlike conventional CPPs, these peptides translocate without energy input and do not rely on endocytosis.
Conclusions:
- A novel class of peptides capable of spontaneous membrane translocation has been discovered.
- These peptides offer a distinct mechanism of cellular entry compared to known CPPs.
- This finding has significant implications for developing new strategies in drug design and delivery, particularly for membrane-impermeant polar drugs.
