The discovery of novel fusion peptides with enhanced properties is crucial for advancing our understanding of membrane fusion processes and developing more efficient tools for biotechnology and medicine. Currently, fusion peptides are mostly identified as portions of viral fusion proteins, and this limits their versatility. This study presents a significant step forward by demonstrating that end-capping a cationic helical peptide with a nucleobase substantially enhances its ability to induce liposome fusion. We show that a helical trichogin analog, Oct-K2569Tric-Lol, containing four lysine residues, induces reversible aggregation of negatively charged liposomes in a concentration-dependent manner. Remarkably, we found that the addition of a single thymine nucleobase at the C-terminus of this peptide (Oct-K2569Tric-T) transforms its activity from reversible aggregation to irreversible membrane fusion. Furthermore, we observed that the presence of complementary nucleobases at both peptide termini promotes membrane fusion even at peptide-to-lipid ratios that do not cause membrane leakage. Our findings provide a new strategy for designing more potent fusion peptides, opening possibilities for improved applications in drug delivery, cell biology research, and nanotechnology.
Morbiato et al. (Wed,) studied this question.