2020 DIG Research Project | “Focused Optimization of Novel Nav1.7 Inhibitors”
Background
Andrey Bortsov, MD, PhD, is a researcher within Duke Anesthesiology’s Center for Translational Pain Medicine (CTPM). He specializes in translational research focused on pain genetics, discovery of new treatment targets, and new analgesic treatment development. Bortsov received his training in medicine from Pavlov Medical University, a leading medical school in Russia. His subsequent PhD from the University of South Carolina provided him with training and expertise in epidemiologic and genetic epidemiologic investigations. During his PhD studies, Bortsov received a two-year pre-doctoral award from the American Heart Association to examine gene-environment interactions influencing obesity. From 2010 - 2016, Bortsov conducted research on pain genetics, pain epidemiology and trauma outcomes at the University of North Carolina in the Department of Anesthesiology. In 2016, he joined Duke’s CTPM, led by Dr. William Maixner. Bortsov is supported by an outstanding research environment, including access to high-quality datasets, clinical patient populations, core facilities, and lead experts in the pain field. Over the past two years, Bortsov, in collaboration with Dr. Ru-Rong Ji, has been working on developing novel Nav1.7 inhibitors by applying computer-aided drug design methods.
Research
Voltage gated sodium channel isoform 1.7 (Nav1.7) is a major subtype of sodium channel in primary sensory neurons, which plays a crucial role in pain transduction. Previous studies have validated Nav1.7 as a promising drug target for new analgesics development. Recent discovery of an extracellularly accessible and isoform-specific pocket on voltage-sensing domain 4 (VSD4) resulted in an array of Nav1.7 inhibitors (e.g. aryl-sulfonamides) that show good isoform selectivity and high efficacy in vitro and in vivo. The binding site has an anion-binding pocket that engages the sulfonamide (the “anionic warhead”), thus defining excellent potency of sulfonamides as Nav1.7 inhibitors. Binding of sulfonamides to the VSD4 binding site promotes or stabilizes an inactivated state of Nav1.7, thus preventing it from propagating depolarization and action potentials in pain-sensing neurons. Unfortunately, sulfonamides have several drawbacks: they activate pregnane X receptor (PXR), inhibit CYP2C9, exert time-dependent inhibition of CYP3A4, and often have high biliary clearance due to polarity, resulting in unfavorable pharmacokinetic profile. There is a need to design new Nav1.7 inhibitors that have high selectivity and potency similar to sulfonamide-based compounds but devoid of their drawbacks.
Bortsov’s research group, in collaboration with Dr. Ru-Rong Ji, has recently identified a novel series of Nav1.7-specific small molecule inhibitors, which inhibit sodium currents in Nav1.7-expressing cell line. Systemic and intrathecal administration of the lead compound substantially reduced formalin-induced inflammatory and paclitaxel-induced neuropathic pain, as well as acute and chronic itch, in murine models. With the help of the Dream Innovation Grant (DIG), made possible through Duke Anesthesiology’s DREAM Campaign, Bortsov and his team expect to generate important preliminary data for future extramural funding applications, with the ultimate goal to develop new non-opioid treatments for pain and itch. New non-opioid analgesics with high selectivity towards Nav1.7 would help overcome the opioid crisis by reducing opioid exposure of pain patients and avoiding serious side effects associated with prolonged opioid use. This would lead to improved patient care and better quality of life.