Abstract：
:γ-Secretase is a multiprotein complex that catalyzes intramembrane proteolysis associated with Alzheimer's disease and cancer. Here, we have developed potent sulfonamide clickable photoaffinity probes that target γ-secretase in vitro and in cells by incorporating various photoreactive groups and walking the clickable alkyne handle to different positions around the molecule. We found that benzophenone is preferred over diazirine as a photoreactive group within the sulfonamide scaffold for labeling γ-secretase. Intriguingly, the placement of the alkyne at different positions has little effect on probe potency but has a significant impact on the efficiency of labeling of γ-secretase. Moreover, the optimized clickable photoprobe, 163-BP3, was utilized as a cellular probe to effectively assess the target engagement of inhibitors with γ-secretase in primary neuronal cells. In addition, biotinylated 163-BP3 probes were developed and used to capture the native γ-secretase complex in the 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate (CHAPSO) solubilized state. Taken together, these next generation clickable and biotinylated sulfonamide probes offer new tools to study γ-secretase in biochemical and cellular systems. Finally, the data provide insights into structural features of the sulfonamide inhibitor binding site in relation to the active site and into the design of clickable photoaffinity probes.
journal_name
ACS Chem Neuroscijournal_title
ACS chemical neuroscienceauthors
Crump CJ,Murrey HE,Ballard TE,Am Ende CW,Wu X,Gertsik N,Johnson DS,Li YMdoi
10.1021/acschemneuro.6b00127subject
Has Abstractpub_date
2016-08-17 00:00:00pages
1166-73issue
8issn
1948-7193journal_volume
7pub_type
杂志文章abstract：:The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, w...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn100093f
更新日期：2011-02-16 00:00:00
abstract：:Exposure to di-(2-ethylhexyl) phthalate (DEHP), a widely used kind of plasticizer, can result in neurodevelopment impairments and learning and memory disorders. We studied the effects and possible mechanisms of maternal DEHP treatment on hippocampal synaptic plasticity in offspring. Pregnant Wistar rats were randomly ...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00612
更新日期：2021-01-20 00:00:00
abstract：:Post-translational modifications of proteins are ubiquitous in living organisms, as they enable an accurate control of the interactions of these macromolecules. For mechanistic studies, it would be highly advantageous to be able to produce in vitro post-translationally modified proteins with site-specificity. Here, we...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00761
更新日期：2021-01-19 00:00:00
abstract：:Glutamate is the major excitatory transmitter in the mammalian CNS, exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn100099n
更新日期：2011-08-17 00:00:00
abstract：:Several chemotherapeutic agents used for cancer treatment induce dose-limiting peripheral neuropathy that compromises patients' quality of life and limits cancer treatment. Recently, mitochondrial dysfunction has been shown to be involved in the mechanism of chemotherapy-induced peripheral neuropathy. SS-20 is a mitoc...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00013
更新日期：2018-07-18 00:00:00
abstract：:Nowadays there are at present no efficient therapies for spinal cord injury (SCI), and new approaches have to be proposed. Recently, a new regenerative medicine strategy has been suggested using smart biomaterials able to carry and deliver cells and/or drugs in the damaged spinal cord. Among the wide field of emerging...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
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abstract：:Bromoalkaloids are secondary metabolites with a demonstrated high activity in several therapeutic areas. In this research, we probe the neuroprotective and antioxidant activities of hymenialdisine and hymenin. Both structures were tested in an oxidative stress cellular model, consisting of cortical neurons that are in...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn500258c
更新日期：2015-02-18 00:00:00
abstract：:Calcitonin gene-related peptide (α-CGRP) released from perivascular sensory nerves induces decreases in diastolic blood pressure (DBP). Experimentally, this can be shown by spinal thoracic (T9-T12) electrical stimulation of these afferent fibers. Because ergotamine inhibits these neurogenic vascular responses and disp...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00611
更新日期：2019-07-17 00:00:00
abstract：:Bipolar disorder is a complex neuropsychiatric disorder, characterized by intermittent episodes of mania and depression. Recent studies have indicated argyrophilic grains, composed of hyperphosphorylated tau, are observable in postmortem brains of bipolar patients. It remains uncertain how tau hyperphosphorylation res...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00629
更新日期：2019-03-20 00:00:00
abstract：:Peripheral immunity is thought to be dysregulated in Parkinson's disease (PD) and may provide an avenue for novel immunotherapeutic interventions. Gut microbiota is a potential factor for modulating immunotherapy response. Considering the possibly complex role of the gut-brain axis in PD, we used a preclinical model t...
journal_title：ACS chemical neuroscience
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doi：10.1021/acschemneuro.0c00386
更新日期：2020-10-21 00:00:00
abstract：:Members of the lysine-specific histone demethylase 5 (KDM5/JARID1) family are known to play important roles in stem cell fate determination. Here, using the KDM5 inhibitor C70 (KDM5-C70), we demonstrated that the histone demethylase activity of the KDM5 enzyme is essential for the repression of astrocytic differentiat...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00613
更新日期：2021-01-22 00:00:00
abstract：:Modulation of the neuropeptide S (NPS) system has been linked to a variety of CNS disorders such as panic disorder, anxiety, sleeping disorders, asthma, obesity, PTSD, and substance abuse. In this study, a series of diphenyltetrahydro-1H-oxazolo[3,4-α]pyrazin-3(5H)-ones were synthesized and evaluated for antagonist ac...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn500113c
更新日期：2014-08-20 00:00:00
abstract：:Photochromic blockers of voltage gated ion channels are powerful tools for the control of neuronal systems with high spatial and temporal precision. We now introduce fotocaine, a new type of photochromic channel blocker based on the long-lasting anesthetic fomocaine. Fotocaine is readily taken up by neurons in brain s...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn500070w
更新日期：2014-07-16 00:00:00
abstract：:The molecular mechanism of protein aggregation is of both fundamental and clinical importance as amyloid aggregates are linked to a number of neurodegenerative disorders. Such protein aggregates include macroscopic insoluble fibrils as well as small soluble oligomeric species. Time-dependent resolution of these specie...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00250
更新日期：2018-12-19 00:00:00
abstract：:The light emission chemistry of firefly luciferase can be harnessed to reveal otherwise invisible biological processes occurring in the brains of live animals. Though powerful, the need for the luciferase substrate D-luciferin to traverse the blood-brain barrier poses limitations on the sensitivity and interpretation ...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.5b00195
更新日期：2015-08-19 00:00:00
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journal_title：ACS chemical neuroscience
pub_type： 历史文章,杂志文章,评审
doi：10.1021/acschemneuro.8b00415
更新日期：2018-10-17 00:00:00
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journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn4001928
更新日期：2014-07-16 00:00:00
abstract：:Aggregation and intracellular deposition of the protein α-synuclein is an underlying characteristic of Parkinson's disease. α-Synuclein assemblies also undergo cell-cell spreading, facilitating propagation of their cellular pathology. Understanding how cellular interactions and uptake of extracellular α-synuclein asse...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.9b00562
更新日期：2020-02-05 00:00:00
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journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00393
更新日期：2019-03-20 00:00:00
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journal_title：ACS chemical neuroscience
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journal_title：ACS chemical neuroscience
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doi：10.1021/cn500020s
更新日期：2015-09-16 00:00:00
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journal_title：ACS chemical neuroscience
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更新日期：2011-11-16 00:00:00
abstract：:The gut is the largest producer of serotonin or 5-hydroxytryptamine (5-HT) in the human body, and 5-HT has been recognized as an important signaling molecule in the gut for decades. There are two distinct sources of enteric 5-HT. Mucosal 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointest...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
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journal_title：ACS chemical neuroscience
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更新日期：2019-07-17 00:00:00
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journal_title：ACS chemical neuroscience
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更新日期：2020-11-04 00:00:00
abstract：:Dopamine (DA) is a neurotransmitter implicated in multiple functions, including movement, cognition, motivation, and reward. The DA transporter (DAT) is responsible for clearing extracellular DA, thereby terminating DA neurotransmission. Previously, it has been shown that insulin signaling through protein kinase B/Akt...
journal_title：ACS chemical neuroscience
pub_type： 信件
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更新日期：2010-07-21 00:00:00
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journal_title：ACS chemical neuroscience
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更新日期：2019-05-15 00:00:00
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journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn200027r
更新日期：2011-05-27 00:00:00
abstract：:The melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors are expressed in the brain and are implicated in the regulation of food intake and energy homeostasis. The endogenous agonist ligands for these receptors (α-, β-, γ-MSH and ACTH) are linear peptides with limited receptor subtype selectivity and metabolic st...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn5000953
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