Current Research and Scholarly Interests
Movement of ions and molecules bi-directionally across cell membranes is a critical requirement for organism survival. When transmembrane transport fails, cells are unable to regulate their internal environment. Many metabolic ligands and drugs have been proven to access and leave cellular interiors through endogenous and energy-dependent influx (entry) and efflux (exit) transport systems. In particular, it is estimated that cell surface transporters play a critical role in regulating intracellular residence (and thus pharmacological impact) of many clinically used drugs.
Cellular transporters are involved in a variety of important physiological processes such as lipid metabolism, ion homeostasis, and immune functions. They are also serve as chaperones for select drug ligands such as antibiotics and calcineurin inhibitors. Overactive transporters are involved in diverse diseases including multidrug resistance, which may limit success of intended drug management of tumors, infectious diseases and seizure disorders. Conversely, underactive transporters may render a cell vulnerable to naturally occurring toxic ligands or other metabolic byproducts that the cell may wish to excrete, potentially hastening cell death or organism death. Defects in these protein transporters have also been causally associated with many human genetic diseases involving accumulation of cellular toxins including Cystic Fibrosis, Tangier Disease, Adrenal Leukodystrophy, and Familial Hyperlipoproteinemia.
Multiple combinations of transport pumps are present on cell surface membranes. Fifteen such transporters have been identified in human pancreatic beta cells and may play a role in multidrug resistance diabetes mellitus.
Through differential activation of tissue transporters, we have created a platform for selective removal of harmful drugs and endogenous substances from unintended tissues and organs. Our novel library of small molecules are optimized to selectively chaperone harmful drugs and cellular byproducts from unintended tissues. This groundbreaking platform technology provides therapeutic opportunities for various drug classes and disease states. To date, we are preparing for Phase 2 human clinical trials with our first novel ligand chaperone.