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
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 hampere...
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Elsevier,
2024-08-01T00:00:00Z.
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| 001 | doaj_403f74994e394d2e9ed2d13b852fc61f | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a Kang Qian |e author |
| 700 | 1 | 0 | |a Peng Yang |e author |
| 700 | 1 | 0 | |a Yixian Li |e author |
| 700 | 1 | 0 | |a Ran Meng |e author |
| 700 | 1 | 0 | |a Yunlong Cheng |e author |
| 700 | 1 | 0 | |a Lingling Zhou |e author |
| 700 | 1 | 0 | |a Jing Wu |e author |
| 700 | 1 | 0 | |a Shuting Xu |e author |
| 700 | 1 | 0 | |a Xiaoyan Bao |e author |
| 700 | 1 | 0 | |a Qian Guo |e author |
| 700 | 1 | 0 | |a Pengzhen Wang |e author |
| 700 | 1 | 0 | |a Minjun Xu |e author |
| 700 | 1 | 0 | |a Dongyu Sheng |e author |
| 700 | 1 | 0 | |a Qizhi Zhang |e author |
| 245 | 0 | 0 | |a 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 |
| 260 | |b Elsevier, |c 2024-08-01T00:00:00Z. | ||
| 500 | |a 1818-0876 | ||
| 500 | |a 10.1016/j.ajps.2024.100938 | ||
| 520 | |a 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. | ||
| 546 | |a EN | ||
| 690 | |a Hybrid peptide | ||
| 690 | |a S-14 G Humanin | ||
| 690 | |a SS31 | ||
| 690 | |a Permeability | ||
| 690 | |a Aβ | ||
| 690 | |a Alzheimer's disease | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Asian Journal of Pharmaceutical Sciences, Vol 19, Iss 4, Pp 100938- (2024) | |
| 787 | 0 | |n http://www.sciencedirect.com/science/article/pii/S1818087624000552 | |
| 787 | 0 | |n https://doaj.org/toc/1818-0876 | |
| 856 | 4 | 1 | |u https://doaj.org/article/403f74994e394d2e9ed2d13b852fc61f |z Connect to this object online. |