RESUMO
Nerve growth factor (NGF) is critical for the proliferation, differentiation, and survival of neurons through its binding to the p75(NTR) and TrkA receptors. Dysregulation of NGF has been implicated in several pathologies, including neurodegeneration (i.e., Parkinson's and Alzheimer's diseases) and both inflammatory and neuropathic pain states. Therefore, small molecule inhibitors that block NGF-receptor interactions have significant therapeutic potential. Small molecule antagonists ALE-0540, PD90780, Ro 08-2750, and PQC 083 have all been reported to inhibit NGF from binding the TrkA receptor. Interestingly, the characterization of the ability of these molecules to block NGF-p75(NTR) interactions has not been performed. In addition, the inhibitory action of these molecules has never been evaluated using surface plasmon resonance (SPR) spectroscopy, which has been proven to be highly useful in drug discovery applications. In the current study, we used SPR biosensors to characterize the binding of NGF to the p75(NTR) receptor in addition to characterizing the inhibitory potential of the known NGF antagonists. The results of this study provide the first evaluation of the ability of these compounds to block NGF binding to p75(NTR) receptor. In addition, only PD90780 was effective at inhibiting the interaction of NGF with p75(NTR), suggesting receptor selectivity between known NGF inhibitors.
Assuntos
Fator de Crescimento Neural/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Receptor de Fator de Crescimento Neural/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Ressonância de Plasmônio de Superfície/métodos , Flavinas , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Fator de Crescimento Neural/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Pteridinas/química , Pteridinas/farmacologia , Receptor de Fator de Crescimento Neural/antagonistas & inibidores , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismoRESUMO
Nerve growth factor (NGF), a member of the neurotrophin family, acts to influence the survival and differentiation of neurons in both the central and peripheral nervous systems via its binding to the p75(NTR) and TrkA receptors. Its precursor, proNGF, has been shown to be the dominant form of NGF in the central nervous system, suggesting a biological function beyond its role as a precursor. Like NGF, proNGF is known to bind the p75(NTR) receptor. The dysregulation of both NGF and proNGF have been implicated in several pathologies, including neurodegenerative diseases linked to p75(NTR)-mediated apoptotic signaling. Therefore, the identification of small molecule inhibitors capable of inhibiting both NGF and proNGF-p75(NTR) interactions may be of therapeutic interest. In the present study, we examine the inhibitory action of known small molecule-based inhibitors PD90780, ALE-0540, Ro 08-2750, and PQC 083, as well as novel derivatives of these compounds, using surface plasmon resonance (SPR) spectroscopy.
