Development of NLRP3 Inflammasome Inhibitors for Neuroinflammatory Conditions

Mount Sinai Health System Background
Neurodegenerative diseases and inflammatory processes are closely involved. The innate immune system utilizes pattern recognition receptors to sense endogenous or exogenous pathogens. Among them, the inflammasome is a high molecular weight protein complex that elicits the activation of inflammatory caspases and processing of pro-interleukin-1b. In neurologic disorders, the NLRP3 inflammasome can induce the secretion of cytokines in microglia and astrocytes, establishing a feedback loop that further mediates neuroinflammation. Unfortunately, there are no effective therapeutic solutions for neurodegenerative diseases, as most treatments are designed to relieve symptoms. For instance, the most extensively used therapy for Amyotrophic Lateral Sclerosis (ALS) is based on riluzole, a neuroprotective drug that extends survival in ALS patients by only 2 or 3 months. Currently, there are no specific inhibitors of NLRP3-inflammasome in clinical use for patients suffering from neurological disorders. Therefore, there is an unmet need to find inhibitors to counteract inflammasome-associated neuronal damage.
Technology Overview
To address this unmet need, investigators have developed small molecule compounds that target the ATP binding domain of the NLRP3 protein complex, thus inhibiting the formation and activation of the NLRP3 inflammasome.
Stage of Development

Designed and optimized small molecules drugs targeting the NLRP3 inflammasome
Demonstrated the effective inhibition of NLRP3 inflammasomes both in vitro and in vivo

Benefits

Inhibitors of NLRP3 protein complex can be used in diverse inflammasome-mediated disorders, including neurodegenerative and autoimmune diseases
No clinical treatment and/or prophylaxis is currently available for NLRP3 inflammasome-mediated disorders

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