| First Author | Qian K | Year | 2024 |
| Journal | Asian J Pharm Sci | Volume | 19 |
| Issue | 4 | Pages | 100938 |
| PubMed ID | 39253611 | Mgi Jnum | J:360716 |
| Mgi Id | MGI:7787205 | Doi | 10.1016/j.ajps.2024.100938 |
| Citation | Qian K, et al. (2024) Rational fusion design inspired by cell-penetrating peptide: SS31/S-14 G Humanin hybrid peptide with amplified multimodal efficacy and bio-permeability for the treatment of Alzheimer's disease. Asian J Pharm Sci 19(4):100938 |
| abstractText | Alzheimer's disease is a neurodegenerative disease induced by multiple interconnected mechanisms. Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology. However, clinical translation of peptide drugs is greatly hampered by their low permeability into brain. Herein, a hybrid peptide HNSS is generated by merging two therapeutic peptides (SS31 and S-14 G Humanin (HNG)), using a different approach from the classical shuttle-therapeutic peptide conjugate design. HNSS demonstrated increased bio-permeability, with a 2-fold improvement in brain distribution over HNG, thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides. HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting, ROS scavenging and p-STAT3 activation. Meanwhile, HNSS with increased Abeta affinity greatly inhibited Abeta oligomerization/fibrillation, and interrupted Abeta interaction with neuron/microglia by reducing neuronal mitochondrial Abeta deposition and promoting microglial phagocytosis of Abeta. In 3x Tg-AD transgenic mice, HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance. This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification, providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease. |
