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

作　　者：Wei Cong Huaxing Shen Xiufei Liao Mengjun Zheng Xianglong Kong Zhe Wang Si Chen Yulei Li Honggang Hu Xiang Li 

机构地区：[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

出　　处：《Acta Pharmaceutica Sinica B》2023年第9期3770-3781,共12页药学学报（英文版）

基　　金：supported by Shanghai Rising-Star Program(to Xiang Li);the National Nature Science Foundation of China No.21807112(to Xiang Li),No.91849129(to Honggang Hu),No.22077078(to Honggang Hu)and No.22207065(to Yulei Li);academic promotion program of Shandong First Medical University(No 2019LJ003,China,to Yulei Li);Taishan Scholars Program(to Yulei Li)。

摘　　要：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).

关 键 词：Stapled peptides OSTEOPOROSIS Orally effective Double-stapling 

分 类 号：R965[医药卫生—药理学]