A mimetic of the mSin3-binding helix of NRSF/REST ameliorates abnormal pain behavior in chronic pain models

Ueda, Hiroshi; Kurita, Jun; Neyama, Hiroyuki; Hirao, Yuuka; Kouji, Hiroyuki; Mishina, Tadashi; Kasai, Masaji; Nakano, Hirofumi; Yoshimori, Atsushi; Nishimura, Yoshifumi

doi:10.1016/j.bmcl.2017.09.006

Cited by 23 publications

(37 citation statements)

References 18 publications

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“…Ueda et al, studied the chemical shift perturbations (CSPs) of the PAH1 domain of Sin3 alone or bound to either NRSF of mS-11. The results strongly supported the notion that mS-11 would supplant NRSF-binding to Sin3, thus interfering with NRSF-Sin3 interaction (38).…”

Section: Discussionsupporting

confidence: 78%

“…However, this reduction was not influenced by either 10 µM ( Fig 3A; Significant main effect of GluR antagonists on two-way ANOVA; F [1,12]= 104.5, p<0.001) or 70 µM concentrations of mS-11 ( Fig 3B; Significant main effect of GluR antagonist on two-way ANOVA; F[1,12]= 15.93, p<0.01). The higher concentration is well in line with those employed in vivo (38) and in vitro (PRISM Co. Datasheet, H. Kouji, personal communication). In addition, this concentration resulted in apparent toxicity within the cultures, suggesting that it is limiting.…”

Section: Ms-11 Does Not Prevent Repression Of Crh Mrna After Ionotropsupporting

confidence: 83%

“…An improved compound called mS-11 was identified. Further details of the compound and its synthesis and testing are provided in Ueda et al, 2017. Because the homology between Sin3A and Sin3B is quite high in the PAH1 domain, mS-11 is expected to interfere with NRSF binding to Sin3A as well.…”

Section: Drug Developmentmentioning

confidence: 99%

“…We then set out to determine if the interaction of NRSF with the cofactor Sin3 is required for NRSF to repress Crh. This was accomplished by the use of a compound designed to mimic the Sin3B-PAH1-interacting domain of NRSF (38).…”

Section: Nrsf Mediates the Repression Of Its Target Gene Crh That Imentioning

confidence: 99%

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NRSF–mediated repression of neuronal genes in developing brain persists in the absence of NRSF-Sin3 interaction

Hall

Short

Singh-Taylor

et al. 2018

Preprint

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¶ These authors contributed equally to this work. AbstractRepression of target genes by the transcriptional repressor neuronal restrictive silencing factor (NRSF)/repressor element 1 silencing transcription factor (REST) contributes to enduring plasticity in the developing brain. However, the cofactor(s) interacting with NRSF to enable target gene repressor are not well understood, and may vary among neuronal populations and brain regions as well as with different contexts. Here we employed the novel designer drug mS-11 to block the interactions of the cofactor Sin3 with NRSF. We tested if NRSF-Sin3 interaction is required for repression of NRSF target genes in developing hypothalamus after activitydependent modulation of NRSF function. In the hypothalamus in vitro, blocking glutamatergic neurotransmission robustly increased NRSF binding to the target gene Crh, resulting in its repression. Blocking the binding of NRSF to the chromatin with decoy NRSEoligodeoxynucleotides abrogated this repression. In contrast, mS-11 at several concentrations did not impede Crh repression. NRSF-mediated repression may underlie disease processes such as the onset of epilepsy. Therefore, identifying small-molecule antagonists of NRSF is crucial for the development of disease-preventing or modifying interventions.

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Section: Discussionsupporting

confidence: 78%

Section: Ms-11 Does Not Prevent Repression Of Crh Mrna After Ionotropsupporting

confidence: 83%

Section: Drug Developmentmentioning

confidence: 99%

Section: Nrsf Mediates the Repression Of Its Target Gene Crh That Imentioning

confidence: 99%

See 2 more Smart Citations

NRSF–mediated repression of neuronal genes in developing brain persists in the absence of NRSF-Sin3 interaction

Hall

Short

Singh-Taylor

et al. 2018

Preprint

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“…Subsequently, it was found to be expressed in pancreatic beta cells 5 and various cancers as a tumor suppressor or oncogenic factor depending on the cell types 6 , 7 . Overexpression of REST/NRSF and/or dysregulation of its cellular expression pattern is related to several neuropathies, including medulloblastoma 8 , 9 (a malignant pediatric brain tumor that originates in the cerebellum or posterior fossa 10 ), glioblastoma 11 , 12 , Huntington’s disease 13 – 16 , neuropathic pain 17 , 18 , and Parkinson’s disease 19 , as well as potentially autism 20 and fibromyalgia 21 .…”

Section: Introductionmentioning

confidence: 99%

Sertraline, chlorprothixene, and chlorpromazine characteristically interact with the REST-binding site of the corepressor mSin3, showing medulloblastoma cell growth inhibitory activities

Kurita

Hirao

Nakano

et al. 2018

Sci Rep

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Dysregulation of repressor-element 1 silencing transcription factor REST/NRSF is related to several neuropathies, including medulloblastoma, glioblastoma, Huntington’s disease, and neuropathic pain. Inhibitors of the interaction between the N-terminal repressor domain of REST/NRSF and the PAH1 domain of its corepressor mSin3 may ameliorate such neuropathies. In-silico screening based on the complex structure of REST/NRSF and mSin3 PAH1 yielded 52 active compounds, including approved neuropathic drugs. We investigated their binding affinity to PAH1 by NMR, and their inhibitory activity toward medulloblastoma cell growth. Interestingly, three antidepressant and antipsychotic medicines, sertraline, chlorprothixene, and chlorpromazine, were found to strongly bind to PAH1. Multivariate analysis based on NMR chemical shift changes in PAH1 residues induced by ligand binding was used to identify compound characteristics associated with cell growth inhibition. Active compounds showed a new chemo-type for inhibitors of the REST/NRSF-mSin3 interaction, raising the possibility of new therapies for neuropathies caused by dysregulation of REST/NRSF.

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Generalized–ensemble method study: A helix‐mimetic compound inhibits protein–protein interaction by long‐range and short‐range intermolecular interactions

et al. 2021

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A heterocyclic compound mS-11 is a helix-mimetic designed to inhibit binding of an intrinsic disordered protein neural restrictive silence factor/repressor element 1 silencing factor (NRSF/REST) to a receptor protein mSin3B. We apply a generalized ensemble method, multi-dimensional virtual-system coupled molecular dynamics developed by ourselves recently, to a system consisting of mS-11 and mSin3B, and obtain a thermally equilibrated distribution, which is comprised of the bound and unbound states extensively. The lowest free-energy position of mS-11 coincides with the NRSF/REST position in the experimentally-determined NRSF/REST-mSin3B complex. Importantly, the molecular orientation of mS-11 is ordering in a wide region around mSin3B. The resultant binding scenario is: When mS-11 is distant from the binding site of mSin3B, mS-11 descends the free-energy slope toward the binding site maintaining the molecular orientation to be advantageous for binding. Then, finally a long and flexible hydrophobic sidechain of mS-11 fits into the binding site, which is the lowest-free-energy complex structure inhibiting NRSF/REST binding to mSin3B.

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A mimetic of the mSin3-binding helix of NRSF/REST ameliorates abnormal pain behavior in chronic pain models

Cited by 23 publications

References 18 publications

NRSF–mediated repression of neuronal genes in developing brain persists in the absence of NRSF-Sin3 interaction

NRSF–mediated repression of neuronal genes in developing brain persists in the absence of NRSF-Sin3 interaction

Sertraline, chlorprothixene, and chlorpromazine characteristically interact with the REST-binding site of the corepressor mSin3, showing medulloblastoma cell growth inhibitory activities

Generalized–ensemble method study: A helix‐mimetic compound inhibits protein–protein interaction by long‐range and short‐range intermolecular interactions

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