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

• Published in: Asian journal of pharmceutical sciences Vol. 19; no. 4; p. 100938
• Main Authors: Qian, Kang, Yang, Peng, Li, Yixian, Meng, Ran, Cheng, Yunlong, Zhou, Lingling, Wu, Jing, Xu, Shuting, Bao, Xiaoyan, Guo, Qian, Wang, Pengzhen, Xu, Minjun, Sheng, Dongyu, Zhang, Qizhi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2024; Shenyang Pharmaceutical University; Elsevier
• Subjects: Alzheimer's disease; Hybrid peptide; Permeability; S-14 G Humanin; SS31; SS31; Hybrid peptide; Aβ; Permeability; Alzheimer's disease; S-14 G Humanin
• ISSN: 1818-0876; 2221-285X; 2221-285X
• DOI: 10.1016/j.ajps.2024.100938

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 Aβ affinity greatly inhibited Aβ oligomerization/fibrillation, and interrupted Aβ interaction with neuron/microglia by reducing neuronal mitochondrial Aβ deposition and promoting microglial phagocytosis of Aβ. In 3× 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. [Display omitted]