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

doi:10.1016/j.apsb.2023.05.004

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

Acta Pharm Sin B. 2023 Sep;13(9):3770-3781. doi: 10.1016/j.apsb.2023.05.004. Epub 2023 May 11.

Authors

Wei Cong¹, Huaxing Shen¹, Xiufei Liao^{2

3}, Mengjun Zheng², Xianglong Kong¹, Zhe Wang⁴, Si Chen¹, Yulei Li⁵, Honggang Hu¹, Xiang Li²

Affiliations

¹ School of Medicine Or Institute of Translational Medicine, Shanghai University, Shanghai 200444, China.
² School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
³ Tarim University, Xinjiang Uygur Autonomous Region, Alar City 843300, China.
⁴ Institute of Bioengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China.
⁵ School of Pharmacy and Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Jinan 250117, China.

Abstract

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).

Keywords: Double-stapling; Orally effective; Osteoporosis; Stapled peptides.