1.Discovery of an orally effective double-stapled peptide for reducing ovariectomy-induced bone loss in mice.
Wei CONG ; Huaxing SHEN ; Xiufei LIAO ; Mengjun ZHENG ; Xianglong KONG ; Zhe WANG ; Si CHEN ; Yulei LI ; Honggang HU ; Xiang LI
Acta Pharmaceutica Sinica B 2023;13(9):3770-3781
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).
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