Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation
Nasir K. Bashiruddin, Mikihito Hayashi, Masanobu Nagano, Yan Wu, Yukiko Matsunaga, Junichi Takagi, Tomoki Nakashima, Hiroaki Suga
Abstract
Significance Osteoporosis affects over 75 million people globally, and this number is increasing with global median age. Therefore, the development of therapeutics with novel mechanisms of action is of high importance. Inhibition of the PlexinB1-Semaphorin4D interaction on osteoblasts has been shown to be a potential target for developing osteoanabolic modalities. Here, using a novel affinity maturation approach for cyclic peptides, we were able to develop cyclic peptide that tightly binds human and mouse PlexinB1 and inhibits its interaction with Semaphorin4D. Chemical dimerization of this peptide resulted in further increases in activity and demonstrated complete rescue of bone loss in an osteoporosis mouse model.