Discovery of an orally effective double-stapled peptide for reducing ovariectomy-induced bone loss in mice

• Published in: Acta pharmaceutica Sinica. B Vol. 13; no. 9; pp. 3770 - 3781
• Main Authors: Cong, Wei, Shen, Huaxing, Liao, Xiufei, Zheng, Mengjun, Kong, Xianglong, Wang, Zhe, Chen, Si, Li, Yulei, Hu, Honggang, Li, Xiang
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.09.2023; Elsevier
• Subjects: Double-stapling; Orally effective; Original; Osteoporosis; Stapled peptides; Osteoporosis; Orally effective; Double-stapling; Stapled peptides
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2023.05.004

Stapled peptides with significantly enhanced pharmacological profiles have emerged as promising therapeutic molecules due to their remarkable resistance to proteolysis and performance to penetrate cells. The all-hydrocarbon peptide stapling technique has already widely adopted with great success, yielding numerous potent peptide-based molecules. Based on our prior efforts, we conceived and prepared a double-stapled peptide in this study, termed FRNC-1, which effectively attenuated the bone resorption capacity of mature osteoclasts in vitro through specific inhibition of phosphorylated GSK-3β. The double-stapled peptide FRNC-1 displayed notably improved helical contents and resistance to proteolysis than its linear form. Additionally, FRNC-1 effectively prevented osteoclast activation and improved bone density for ovariectomized (OVX) mice after intravenous injection and importantly, after oral (intragastric) administration. The double-stapled peptide FRNC-1 is the first orally effective peptide that has been validated to date as a therapeutic candidate for postmenopausal osteoporosis (PMOP). The double-stapled peptide FRNC-1 is for the first time identified as the orally effective peptide a therapeutic candidate for postmenopausal osteoporosis (PMOP). [Display omitted]