Small, nonpeptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death.
Studies showing that neurotrophin binding to p75NTR can promote cell survival in the absence of Trk (tropomyosin-related kinase) receptors, together with recent structural data indicating that NGF may bind to p75NTR in a monovalent manner, raise the possibility that small molecule p75NTR ligands that positively regulate survival might be found. A pharmacophore designed to capture selected structural and physical chemical features of a neurotrophin domain known to interact with p75NTR was applied to in silico screening of small molecule libraries. Small, nonpeptide, monomeric compounds were identified that interact with p75NTR. In cells showing trophic responses to neurotrophins, the compounds promoted survival signaling through p75NTR-dependent mechanisms. In cells susceptible to proneurotrophin-induced death, compounds did not induce apoptosis but inhibited proneurotrophin-mediated death. These studies identify a unique range of p75NTR behaviors that can result from isolated receptor liganding and establish several novel therapeutic leads.
Massa
Stephen M
SM
Department of Neurology, San Francisco Veterans Affairs Medical Center, San Francisco, California 94121, USA. Stephen.Massa@ucsf.edu
Xie
Youmei
Y
Yang
Tao
T
Harrington
Anthony W
AW
Kim
Mi Lyang
ML
Yoon
Sung Ok
SO
Kraemer
Rosemary
R
Moore
Laura A
LA
Hempstead
Barbara L
BL
Longo
Frank M
FM
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007532:Isoleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D008970:Molecular Weight; D009025:Morpholines / Q000494:pharmacology; D041681:NIH 3T3 Cells; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009414:Nerve Growth Factors / Q000138:chemical synthesis / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D011498:Protein Precursors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
C575077:LM11A-31; D008024:Ligands; D009025:Morpholines; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; C489226:pro-nerve growth factor, mouse; D007532:Isoleucine; D020932:Nerve Growth Factor