Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation
| العنوان: | Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation |
|---|---|
| المؤلفون: | Masanobu Nagano, Hiroaki Suga, Junichi Takagi, Yukiko Matsunaga, Yan Wu, Nasir K Bashiruddin, Mikihito Hayashi, Tomoki Nakashima |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Anabolism, Ovariectomy, Osteoporosis, Parathyroid hormone, Pharmacology, Peptides, Cyclic, 01 natural sciences, Bone resorption, Affinity maturation, 03 medical and health sciences, Osteogenesis, Peptide Library, In vivo, medicine, Animals, Humans, Amino Acid Sequence, Femur, 030304 developmental biology, 0303 health sciences, Multidisciplinary, 010405 organic chemistry, Chemistry, cyclic peptides, Osteoblast, X-Ray Microtomography, Biological Sciences, medicine.disease, osteoporosis, 0104 chemical sciences, Mice, Inbred C57BL, medicine.anatomical_structure, Animals, Newborn, in vitro selection, Ovariectomized rat, Applied Biological Sciences, PlexinB1, Protein Multimerization |
| الوصف: | 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. Osteoporosis is caused by a disequilibrium between bone resorption and bone formation. Therapeutics for osteoporosis can be divided into antiresorptives that suppress bone resorption and anabolics which increase bone formation. Currently, the only anabolic treatment options are parathyroid hormone mimetics or an anti-sclerostin monoclonal antibody. With the current global increases in demographics at risk for osteoporosis, development of therapeutics that elicit anabolic activity through alternative mechanisms is imperative. Blockade of the PlexinB1 and Semaphorin4D interaction on osteoblasts has been shown to be a promising mechanism to increase bone formation. Here we report the discovery of cyclic peptides by a novel RaPID (Random nonstandard Peptides Integrated Discovery) system-based affinity maturation methodology that generated the peptide PB1m6A9 which binds with high affinity to both human and mouse PlexinB1. The chemically dimerized peptide, PB1d6A9, showed potent inhibition of PlexinB1 signaling in mouse primary osteoblast cultures, resulting in significant enhancement of bone formation even compared to non-Semaphorin4D–treated controls. This high anabolic activity was also observed in vivo when the lipidated PB1d6A9 (PB1d6A9-Pal) was intravenously administered once weekly to ovariectomized mice, leading to complete rescue of bone loss. The potent osteogenic properties of this peptide shows great promise as an addition to the current anabolic treatment options for bone diseases such as osteoporosis. |
| تدمد: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2012266117 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f220681f9bddb3bf933dd8d79fd2bcb5 https://doi.org/10.1073/pnas.2012266117 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f220681f9bddb3bf933dd8d79fd2bcb5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
|---|---|
| DOI: | 10.1073/pnas.2012266117 |