Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 30, Issue 12, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2020.127190
Keywords
Epsin N-terminal segment; Trimerization; Membrane curvature; Lipid packing; Oligoarginine; Cell-membrane penetration
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Funding
- Pharmaceutical Society of Japan
- Suntory Foundation for Life Sciences
- JSPS KAKENHI [JP18H04547, 18H04017]
- Collaborative Research Program of the Institute for Chemical Research, Kyoto University [2019-78]
- Helmholtz Association Program BIF-TM
- German Research Foundation (DFG) [UL127/7-1, INST 121384/58-1 FUGG]
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Modulating the structural dynamics of biomembranes by inducing bilayer curvature and lipid packing defects has been highlighted as a practical tool to modify membrane-dependent cellular processes. Previously, we have reported on an amphipathic helical peptide derived from the N-terminal segment (residues 1-18, EpN18) of epsin-1, which can promote membrane remodeling including lipid packing defects in cell membranes. However, a high concentration is required to exhibit a pronounced effect. In this study, we demonstrate a significant increase in the membrane-remodeling effect of EpN18 by constructing a branched EpN18 homotrimer. Both monomer and trimer could enhance cell internalization of octaarginine (R8), a cell-penetrating peptide. The EpN18 trimer, however, promoted the uptake of R8 at an 80-fold lower concentration than the monomer. Analysis of the generalized polarization of a polarity-sensitive dye (di-4-ANEPPDHQ) revealed a higher efficacy of trimeric EpN18 in loosening the lipid packing in the cell membrane. Circular dichroism measurements in the presence of lipid vesicles showed that the EpN18 trimer has a higher alpha-helix content compared with the monomer. The stronger ability of the EpN18 trimer to impede negative bilayer curvature is also corroborated by solid-state P-31 NMR spectroscopy. Hence, trimerizing peptides can be considered a promising approach for an exponential enhancement of their membrane-remodeling performance.
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