Savannah Biby, Prasenjit Mondal, Yiming Xu, Ashley Gomm, Baljit Kaur, Jannatun N. Namme, Changning Wang, Rudolph E. Tanzi, Shijun Zhang, Can Zhang
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Functional Characterization of an Arylsulfonamide-Based Small-Molecule Inhibitor of the NLRP3 Inflammasome
Considerable evidence indicates that the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays key roles in human pathophysiology, suggesting it as a potential drug target. Currently, studies have yet to develop compounds that are promising therapeutics in the clinic by targeting the NLRP3 inflammasome. Herein, we aim to further biologically characterize a previously identified small-molecule inhibitor of the NLRP3 inflammasome from our group, YM-I-26, to confirm its functional activities. We showed that YM-I-26 is highly selective toward the NLRP3 inflammasome and binds to NLRP3 directly. A systemic analysis revealed YM-I-26 with inflammation-related and immunomodulatory activities by the Eurofins BioMAP Diversity PLUS panel. In addition, studies using the mouse microglia BV2 cell model demonstrated that YM-I-26 is not cytotoxic, improved the phagocytotic functions of BV2 cells toward beta-amyloid, and suppressed the production of cytokines of IL-1β and IL-10 upon the activation of the NLRP3 inflammasome. Collectively, our studies support the functional activities of YM-I-26 as a NLRP3 inhibitor in physiologically relevant cell models, and warrant future studies of YM-I-26 and its analogs to advance the drug development as potential therapeutics.
期刊介绍:
ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following:
Neurotransmitters and receptors
Neuropharmaceuticals and therapeutics
Neural development—Plasticity, and degeneration
Chemical, physical, and computational methods in neuroscience
Neuronal diseases—basis, detection, and treatment
Mechanism of aging, learning, memory and behavior
Pain and sensory processing
Neurotoxins
Neuroscience-inspired bioengineering
Development of methods in chemical neurobiology
Neuroimaging agents and technologies
Animal models for central nervous system diseases
Behavioral research