Targeting PDZ domain proteins for treating NMDA receptor-mediated excitotoxicity.
N-methyl-D-aspartate (NMDA) receptors play essential roles in the normal physiology of neurons, and these receptors are also largely responsible for glutamate-induced excitotoxicity. Since treatments of glutamate-induced excitotoxicity by NMDA receptor inhibitors often result in adverse side effects, alternative treatment approaches have been actively sought in recent years. One potential approach is to target proteins and enzymes down stream of the NMDA receptor signaling pathways. Extensive studies in recent years have demonstrated that PDZ domains of PSD-95 play critical roles in scaffolding the NMDA receptor/neuronal nitric oxide synthase pathway. Therefore, PSD-95 PDZ domains become attractive targets for treatment of glutamate-induced overproduction of nitric oxide. The strategy is to develop small compounds that can effectively block protein-protein interactions mediated by the PDZ domains of PSD-95. Biochemical and structural studies of PDZ/target interactions have indicated that developing small molecules to compete with PDZ targets is a feasible approach. We provide an example demonstrating the discovery and further development of small molecules capable of disrupting PSD-95/NMDA receptor and/or PSD-95/neuronal nitric oxide synthase complexes.
Wen
Wenyu
W
Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR China.
Wang
Wenning
W
Zhang
Mingjie
M
D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008958:Models, Molecular; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D011487:Protein Conformation; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology*; D015398:Signal Transduction
C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D052248:Nitric Oxide Synthase Type I