Selective small molecule peptidomimetic ligands of TrkC and TrkA receptors afford discrete or complete neurotrophic activities

• Main Authors: Maria Clara Zaccaro, Boon Lee Hong, Mookda Pattarawarapan, Zebin Xia, Antoine Caron, Pierrre Jean L'Heureux, Yoshua Bengio, Kevin Burgess, H. Uri Saragovi
• Format: Journal
• Published: 2018
• Subjects: Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics
• Online Access: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=25144497042&origin=inward; http://cmuir.cmu.ac.th/jspui/handle/6653943832/62092
• Institution: Chiang Mai University

We designed a minilibrary of 55 small molecule peptidomimetics based on β-turns of the neurotrophin growth factor polypeptides neurotrophin-3 (NT-3) and nerve growth factor (NGF). Direct binding, binding competition, and biological screens identified agonistic ligands of the ectodomain of the neurotrophin receptors TrkC and TrkA. Agonism is intrinsic to the peptidomimetic ligand (in the absence of neurotrophins), and/or can also be detected as potentiation of neurotrophin action. Remarkably, some peptidomimetics afford both neurotrophic activities of cell survival and neuronal differentiation, while others afford discrete signals leading to either survival or differentiation. The high rate of hits identified suggests that focused minilibraries may be desirable for developing bioactive ligands of cell surface receptors. Small, selective, proteolytically stable ligands with defined biological activity may have therapeutic potential. ©2005 Elsevier Ltd All rights reserved.