AKulkarni-01
Novel NLRP3 inflammasome inhibitors for the treatment of HIV-Associated Neurocognitive Disorders (HAND)
Dr. Amol Kulkarni
Health, human disease & diagnostics
Preferred major field of study or minimum required skills
Synthetic chemistry, retrosynthetic analysis, basic analytical chemistry, Nuclear magnetic resonance spectroscopy, Infrared spectroscopy, Mass spectroscopy, Chromatography.
Scholarly significance/intellectual merit
Neurological dysfunction is one of the most common comorbidities seen in chronic HIV patients. Inflammation plays a critical role in the HAND pathophysiology. The project focuses on one of the main regulators of inflammatory response in HIV-1 infection, the NLRP3 inflammasome. The NLRP3 inflammasome is a cytosolic complex that is activated in chronic HIV infection leading to increased expression and protein levels of proinflammatory cytokines, such as, IL-1b and IL-18. Small molecules that disrupt the NLRP3 signaling have been shown to attenuate neuroinflammation and neuronal pyroptosis in transgenic mouse model of HIV. Our prior research has identified a small molecule inhibitor of the NLRP3 inflammasome, AMS-17. Because of its unique structure, AMS-17 does not display severe adverse effects commonly seen in NLRP3 inflammasome inhibitors. Currently we are exploring computationally-guided library of AMS-17 analogues with improved NLRP3 inflammasome inhibitory activity while maintaining low toxicity and high selectivity.
Research question(s)
Question: What structural motif(s) are necessary for potent, selective NLRP3 inflammasome inhibitory activity?
Objective: To create a computationally-guided library of NLRP3 inflammasome inhibitors with potent activity, low toxicity, and enhanced ability to cross the blood-brain barrier.
Methods/techniques/instruments to be learned/utilized
Methods: retrosynthetic analysis, synthesis, isolation, purification, and characterization of small molecules.
Instruments: NMR, IR, Mass Spectroscopy and HPLC