title: Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.
abstract: A library of peptidomimetics was assembled combinatorially into dimers on a triazine-based core. The pharmacophore corresponds to β-turns of the neurotrophin polypeptides neurotrophin-3 (NT-3), nerve growth factor (NGF), or brain-derived neurotrophic factor (BDNF). These are the natural ligands for TrkC, TrkA, and TrkB receptors, respectively. The linker length and the side-chain orientation of each monomer within the bivalent mimics were systematically altered, and the impact of these changes on the function of each ligand was evaluated. While the monovalent peptidomimetics had no detectable binding or bioactivity, four bivalent peptidomimetics (2c, 2d, 2e, 3f) are selective TrkC ligands with antagonistic activity, and two bivalent peptidomimetics (1a, 1b) are TrkC and TrkA ligands with antagonistic activity. All these bivalent compounds block ligand-dependent receptor activation and cell survival, without affecting neuritogenic differentiation. This work adds to our understanding of how the neurotrophins function through Trk receptors, and demonstrates that peptidomimetics can be designed to selectively disturb specific biological signals, and may be used as pharmacological probes or as therapeutic leads. The concept of altering side-chain, linker length, and sequence orientation of a subunit within a pharmacophore provides an easy modular approach to generate larger libraries with diversified bioactivity.
authors.affiliation: Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Fouad
authors.initials: F
authors.lastname: Brahimi
authors.affiliation: Department of Chemistry, Texas A&M University. Texas, United States of America.
authors.forename: Eunhwa
authors.initials: E
authors.lastname: Ko
authors.affiliation: Department of Chemistry, Texas A&M University. Texas, United States of America.
authors.forename: Andrey
authors.initials: A
authors.lastname: Malakhov
authors.affiliation: Department of Chemistry, Texas A&M University. Texas, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Burgess
authors.affiliation: Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; Department of Oncology and the Cancer Center, McGill University, Montreal, Quebec, Canada.
authors.forename: H Uri
authors.initials: HU
authors.lastname: Saragovi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D020932:Nerve Growth Factor / Q000737:chemistry / Q000494:pharmacology; D020933:Neurotrophin 3 / Q000737:chemistry / Q000494:pharmacology; D016716:PC12 Cells; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020917:Receptor, trkA / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020812:Receptor, trkC / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020933:Neurotrophin 3; D057786:Peptidomimetics; D054852:Small Molecule Libraries; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020812:Receptor, trkC