A mimetic of the mSin3-binding helix of NRSF/REST ameliorates abnormal pain behavior in chronic pain models
| Autor: | Yuuka Hirao, Hiroyuki Neyama, Atsushi Yoshimori, Hirofumi Nakano, Yoshifumi Nishimura, Hiroshi Ueda, Masaji Kasai, Jun-ichi Kurita, Tadashi Mishina, Hiroyuki Kouji |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Clinical Biochemistry Pharmaceutical Science Pharmacology Heterocyclic Compounds 2-Ring Biochemistry Protein Structure Secondary Mice 03 medical and health sciences 0302 clinical medicine Protein Domains Fibromyalgia Internal medicine Drug Discovery Gene expression medicine Animals Gene silencing Molecular Biology Rest (music) Binding Sites Morphine Chemistry Organic Chemistry Chronic pain medicine.disease Peripheral Analgesics Opioid Cold Temperature Molecular Docking Simulation Repressor Proteins Disease Models Animal 030104 developmental biology Endocrinology Neuropathic pain Neuralgia Molecular Medicine Chronic Pain Pain behavior Carrier Proteins 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 27:4705-4709 |
| ISSN: | 0960-894X |
| Popis: | The neuron-restrictive silencing factor NRSF/REST binds to neuron-restrictive silencing elements in neuronal genes and recruits corepressors such as mSin3 to inhibit epigenetically neuronal gene expression. Because dysregulation of NRSF/REST is related to neuropathic pain, here, we have designed compounds to target neuropathic pain based on the mSin3-binding helix structure of NRSF/REST and examined their ability to bind to mSin3 by NMR. One compound, mS-11, binds strongly to mSin3 with a binding mode similar to that of NRSF/REST. In a mouse model of neuropathic pain, mS-11 was found to ameliorate abnormal pain behavior and to reverse lost peripheral morphine analgesia. Furthermore, even in the less well epigenetically defined case of fibromyalgia, mS-11 ameliorated symptoms in a mouse model, suggesting that fibromyalgia is related to the dysfunction of NRSF/REST. Taken together, these findings show that the chemically optimized mimetic mS-11 can inhibit mSin3-NRSF/REST binding and successfully reverse lost peripheral and central morphine analgesia in mouse models of pain. |
| Databáze: | OpenAIRE |
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