Neuroprotective Effect of <i>N</i>-Cyclohexylethyl-[A/G]-[D/E]-X-V Peptides on Ischemic Stroke by Blocking nNOS–CAPON Interaction

Qin, Yajuan; Feng, Lingling; Fan, Xin; Zheng, Liping; Zhang, Yu; Chang, Lei; Li, Tingyou

doi:10.1021/acschemneuro.0c00739

Cited by 6 publications

(3 citation statements)

References 34 publications

(65 reference statements)

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“…To further examine the role of SERT-nNOS coupling in the DRN as it relates to depression, we screened our compound library previously established on the basis of nNOS-mediated protein-protein interactions, some of which has been published previously ( 23 – 26 ). Unexpectedly, we found that two compounds of the Sakura series (fig.…”

Section: Resultsmentioning

confidence: 99%

Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN

Sun

Qin

Chu

et al. 2022

Science

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Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD.

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Section: Resultsmentioning

confidence: 99%

Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN

Sun

Qin

Chu

et al. 2022

Science

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“…2e). Increased mRNA levels of the Wnt target genes Axin2, LEF1, and Bmp2 (Riese et al, 1997;Jho et al, 2002;Lewis et al, 2010) were induced by Wnt3a treatment, as measured by qRT-PCR, and these increases were reduced by compounds 18, 20, and 21 (Fig. 2f).…”

Section: Comparison To Reported Dvl Pdz-binding Molecule Subsectionmentioning

confidence: 94%

Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling

et al. 2021

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Abstract. Dishevelled (Dvl) proteins are important regulators of the Wnt signalling pathway, interacting through their PDZ domains with the Wnt receptor Frizzled. Blocking the Dvl PDZ–Frizzled interaction represents a potential approach for cancer treatment, which stimulated the identification of small-molecule inhibitors, among them the anti-inflammatory drug Sulindac and Ky-02327. Aiming to develop tighter binding compounds without side effects, we investigated structure–activity relationships of sulfonamides. X-ray crystallography showed high complementarity of anthranilic acid derivatives in the GLGF loop cavity and space for ligand growth towards the PDZ surface. Our best binding compound inhibits Wnt signalling in a dose-dependent manner as demonstrated by TOP-GFP assays (IC50∼50 µM) and Western blotting of β-catenin levels. Real-time PCR showed reduction in the expression of Wnt-specific genes. Our compound interacted with Dvl-1 PDZ (KD=2.4 µM) stronger than Ky-02327 and may be developed into a lead compound interfering with the Wnt pathway.

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“…Uncoupling nNOS-CAPON inhibits the excitotoxic activation of p38MAPK and subsequent neuronal death [ 119 ]. The nNOS-CAPON inhibitor N-cyclohexylethyl-AD(OMe)AV, designed by targeting the PDZ of nNOS, has a neuroprotective effect on ischemic stroke in rats [ 120 ]. Interestingly, it has been reported that the CAPON PDZ ligand motif does not bind to nNOS, and in contrast, full-length CAPON forms an unusually stable interaction with nNOS.…”

Section: Nnos-capon Interaction and Neurological Diseasesmentioning

confidence: 99%

nNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story

Zhu

2023

Neurosci. Bull.

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In the central nervous system, nitric oxide (NO), a free gas with multitudinous bioactivities, is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase (nNOS). In the past 20 years, the studies in our group and other laboratories have suggested a significant involvement of nNOS in a variety of neurological and neuropsychiatric disorders. In particular, the interactions between the PDZ domain of nNOS and its adaptor proteins, including post-synaptic density 95, the carboxy-terminal PDZ ligand of nNOS, and the serotonin transporter, significantly influence the subcellular localization and functions of nNOS in the brain. The nNOS-mediated protein-protein interactions provide new attractive targets and guide the discovery of therapeutic drugs for neurological and neuropsychiatric disorders. Here, we summarize the work on the roles of nNOS and its association with multiple adaptor proteins on neurological and neuropsychiatric disorders.

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Neuroprotective Effect of N-Cyclohexylethyl-[A/G]-[D/E]-X-V Peptides on Ischemic Stroke by Blocking nNOS–CAPON Interaction

Cited by 6 publications

References 34 publications

Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN

Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN

Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling

nNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story

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