New templates for syntheses of ring-fused, C(10) beta-turn peptidomimetics leading to the first reported small-molecule mimic of neurotrophin-3.
beta-Turn peptidomimetics 1 were designed to mimic hot spots of neurotrophin-3 (NT-3) and others. Solid-phase syntheses of these were developed, though limitations were encountered with scale-up. Consequently, an alternative design with 2 was investigated. 1 and 2 favored distorted type I beta-turn conformations in solution. It was found that peptidomimetic 2b has NT-3-like neurotrophic activity in cell survival assays, selectively binds the NT-3 receptor TrkC, and induces the tyrosine phosphorylation of the TrkC receptor.
Pattarawarapan
Mookda
M
Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas 77842-3012, USA.
Zaccaro
Maria Clara
MC
Saragovi
Uri H
UH
Burgess
Kevin
K
D016475:3T3 Cells; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D005434:Flow Cytometry; D051379:Mice; D018716:Molecular Mimicry; D020933:Neurotrophin 3 / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D020917:Receptor, trkA / Q000378:metabolism; D020812:Receptor, trkC / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D020933:Neurotrophin 3; D010455:Peptides; D010456:Peptides, Cyclic; C466634:cyclo(lysyl-serinamido-4-carbamoylphenylmethylamino-3-nitrobenzoyl); D014443:Tyrosine; D020917:Receptor, trkA; D020812:Receptor, trkC