mS-11, a mimetic of the mSin3-binding helix in NRSF, ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model

Kawase, Haruki; Ago, Yukio; Naito, Masashi; Higuchi, Momoko; Hara, Yuta; Hasebe, Shigeru; Tsukada, Shinji; Kasai, Atsushi; Nakazawa, Takahiro; Mishina, Tadashi; Kouji, Hiroyuki; Takuma, Kazuhiro; Hashimoto, Hitoshi

doi:10.1016/j.pbb.2018.11.003

Cited by 11 publications

(4 citation statements)

References 40 publications

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“…Compound 12a is confirmed to interact with mSin3, inhibiting mSin3-NRSF/REST binding by NMR analysis (PDB ID: 5Y95) . It also ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model . Detailed in silico analysis by enhanced molecular dynamics simulation revealed that this scaffold induced PPI inhibition by long-range molecular orientation ordering followed by short-range interactions …”

Section: Introductionmentioning

confidence: 98%

“…25 It also ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model. 29 Detailed in silico analysis by enhanced molecular dynamics simulation revealed that this scaffold induced PPI inhibition by long-range molecular orientation ordering followed by short-range interactions. 30 Although many structural peptidomimetics have been developed, no analytical or validation method has been established to demonstrate quantitatively how similarly these molecules can mimic target peptide structures.…”

Section: ■ Introductionmentioning

confidence: 99%

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Visualized and Quantitative Conformational Analysis of Peptidomimetics

Takashima

Yoshimori²,

Honda

et al. 2021

ACS Omega

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Protein−protein interactions (PPIs) are fundamentally important and challenging drug targets. Peptidomimetic molecules of various types have been developed to modulate PPIs. A particularly promising drug discovery strategy, structural peptidomimetics, was designed based on special mimicking of sidechain C α −C β bonds. It is simple and versatile. Nevertheless, no quantitative method has been established to evaluate its similarity to a target peptide motif. We developed two methods that enable visual, comprehensive, and quantitative analysis of peptidomimetics: peptide conformation distribution (PCD) plot and peptidomimetic analysis (PMA) map. These methods specifically examine multiple side-chain C α −C β bonds of a peptide fragment motif and their corresponding bonds (pseudo-C α −C β bonds) in a mimetic molecule instead of φ and ψ angles of a single amino acid in the traditional Ramachandran plot. The PCD plot is an alignment-free method, whereas the PMA map is an alignment-based method providing distinctive and complementary analysis. Results obtained from analysis using these two methods indicate our multifacial α-helix mimetic scaffold 12 as an excellent peptidomimetic that can precisely mimic the spatial positioning of side-chain functional groups of α-helix. These methods are useful for visualized and quantified evaluation of peptidomimetics and for the rational design of new mimetic scaffolds.

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Section: Introductionmentioning

confidence: 98%

Section: ■ Introductionmentioning

confidence: 99%

Visualized and Quantitative Conformational Analysis of Peptidomimetics

Takashima

Yoshimori²,

Honda

et al. 2021

ACS Omega

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“…For instance, the small molecule mS-11 was designed based on the mSin3binding helix structure of REST. It inhibits mSin3-REST binding to reverse pain and autism in mice models [271][272][273]. The quinolone-like compound 91 (C91) was discovered by virtual screening.…”

Section: Targeting Restmentioning

confidence: 99%

REST Is Not Resting: REST/NRSF in Health and Disease

Jin,

Liu,

et al. 2023

Biomolecules

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Chromatin modifications play a crucial role in the regulation of gene expression. The repressor element-1 (RE1) silencing transcription factor (REST), also known as neuron-restrictive silencer factor (NRSF) and X2 box repressor (XBR), was found to regulate gene transcription by binding to chromatin and recruiting chromatin-modifying enzymes. Earlier studies revealed that REST plays an important role in the development and disease of the nervous system, mainly by repressing the transcription of neuron-specific genes. Subsequently, REST was found to be critical in other tissues, such as the heart, pancreas, skin, eye, and vascular. Dysregulation of REST was also found in nervous and non-nervous system cancers. In parallel, multiple strategies to target REST have been developed. In this paper, we provide a comprehensive summary of the research progress made over the past 28 years since the discovery of REST, encompassing both physiological and pathological aspects. These insights into the effects and mechanisms of REST contribute to an in-depth understanding of the transcriptional regulatory mechanisms of genes and their roles in the development and progression of disease, with a view to discovering potential therapeutic targets and intervention strategies for various related diseases.

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“…Importantly, this compound ameliorates abnormal pain behavior in a mouse chronic pain model 24 and social interaction deficits in a prenatal valproic acid-induced autism mouse model. 25 The compound mS-11 has shown to bind to mSin3 by NMR binding experiments 24 and a binding model is proposed using a computer program, HADDOCK. 26 In the resultant model (PDB ID: 5Y95), mS-11 bound in the cleft of mSin3B but sunk in a considerably deeper position than the position of the LIML sequence in the NMR structure of the NRSF/REST-mSin3B complex.…”

mentioning

confidence: 99%

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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mS-11, a mimetic of the mSin3-binding helix in NRSF, ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model

Cited by 11 publications

References 40 publications

Visualized and Quantitative Conformational Analysis of Peptidomimetics

Visualized and Quantitative Conformational Analysis of Peptidomimetics

REST Is Not Resting: REST/NRSF in Health and Disease

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

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