Development of chemical tools for allosteric regulation of human liver pyruvate kinase. A Potential Path toward Novel Treatment of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver problems in the world today and there are no drugs for NAFLD.Systems level analysis has indicated that the gene encoding liver-specific pyruvate kinase is a target for the development of effective treatment strategy for NAFLD.There are four isoforms of PK in humans, which are allosterically regulated by various physiological modulators.

The differences in the structure around the allosteric binding sites can be exploited to develop cell type-selective modulators.This project aims to develop selective human PKL modulators as tools for probing the allosteric regulation of PKL, and as lead compounds for potential treatment of NAFLD.We will explore fragment-based drug discovery methods to develop PKL modulators and to investigate the shape and physicochemical properties of the allosteric site for opportunities to merge, link and grow suitable fragments into new modulators.We will use cryo-electron microscopy and hydrogen-deuterium exchange mass spectrometry to capture the oligomeric structure of PKL in several dynamic states with and without the modulators present.We will develop biochemical and cellular affinity assays to measure the binding of modulators to PKL.We are not aware of any other research group that focuses on the development of PKL modulators or has PKL as a target for the development of drugs for the treatment of NAFLD.