Stimulation of N-cadherin-dependent neurite outgrowth by small molecule peptide mimetic agonists of the N-cadherin HAV motif.
N-cadherin is a cell adhesion molecule that promotes axon outgrowth and synapse formation during the development of the central nervous system. In addition, N-cadherin promotes glial cell adhesion and myelination of axons. Therefore, stimulating N-cadherin function with N-cadherin agonists could be used therapeutically to promote regeneration of the nervous system and remyelination after injury or disease. In the extracellular domain of N-cadherin, the amino acid sequence HAV is required for N-cadherin-mediated adhesion and neurite outgrowth. The ADH-1 cyclic peptide, derived from the N-cadherin HAV site, is an effective antagonist of N-cadherin-mediated neurite outgrowth and is currently being tested in clinical trials for cancer chemotherapy. Of interest, a dimeric version of this cyclic peptide, N-Ac-CHAVDINGHAVDIC-NH(2), functions as an N-cadherin agonist. This dimeric peptide agonist and the peptide antagonist ADH-1 both have limitations as drugs due to their metabolic instability and lack of oral delivery. To address this issue Adherex Technologies Inc. generated a small molecule library of peptidomimetics to the HAV region of N-cadherin, which would be more amenable to therapeutic use. We screened the Adherex library for compounds that altered neurite outgrowth and identified eight N-cadherin agonists that stimulated N-cadherin-dependent neurite outgrowth. Five of these agonists also stimulated retinal cell migration. These small molecule agonists may be effective reagents for promoting axon growth and remyelination after injury or disease.
Department of Molecular Biology & Microbiology, Case Western Reserve University, Cleveland, OH 44106, United States. susann.brady-kalnay@case.edu
Susan M
SM
Burden-Gulley
Theresa J
TJ
Gates
Sonya E L
SE
Craig
Mukur
M
Gupta
Susann M
SM
Brady-Kalnay
D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D015394:Molecular Structure; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012160:Retina / Q000166:cytology; D046509:Tissue Culture Techniques
D015820:Cadherins; D010455:Peptides