Small molecule modulators of PPARγ as new diabetes drugs

Synthetic full agonists of PPARγ have been prescribed for the treatment of diabetes due to their ability to regulate glucose homeostasis and insulin sensitization. While the use of full agonists of PPARγ has been hampered due to severe side effects, partial agonists, antagonists, and inverse agonists have shown promise due to their decreased incidence of such side effects in preclinical models. No kinetic information has been forthcoming in regard to the mechanism of full versus partial agonism of PPARγ to date and little structural and dynamic information is available which can shed light on the mechanistic difference between full and partial agonists as well as antagonists. We have used X-ray crystallography, cellular assays, Hydrogen Deuterium Exchange (HDX), and Surface Plasmon Resonance (SPR) to probe the mechanism of several PPARγ small molecule modulators to uncover PPARγ structural mechanisms and to aid in structure guided drug design. Our findings demonstrate that not only do partial agonists and inverse agonists/antagonists act through distinct transcriptional mechanisms, they also demonstrate differences in structure, dynamics, and kinetics as compared to full agonists. 

John B. Bruning is currently employed as a Senior Lecturer (with tenure) at the University of Adelaide where he heads the Laboratory of Protein Crystallography. He obtained his PhD at Rice University and completed two post-doctoral fellowships: one at the Scripps Research Institute and one at Texas A&M University. While at the Scripps Research Institute he spearheaded research on defining nuclear receptor allostery and structure guided drug design which he carried out in a world renowned research environment. He conceived and carried out many multidisciplinary projects interacting with chemists, microbiologists, biochemists, endocrinologists, and structural biologists. While at Texas A&M University he played an integral part in the TB consortium and used the crystallographic facilities and mentoring available to solve more than 30 protein structures. In August 2012 he earned a highly competitive Lecturer faculty position in the School of Molecular and Biomedical Science (now the School of Biological Sciences) at the University of Adelaide. He has created and manages the first macromolecular crystal pipeline at the University of Adelaide North Terrace. CI Bruning is an expert in multiple areas of structural biology, especially in regard to the application of X-ray crystallography to understanding human disease. His work has been focused on areas such as protein sensor modulation, allostery, structure guided drug design, and protein structure using novel multidisciplinary approaches. He has characterized biochemical systems of varied but related areas such as nuclear receptors, DNA replication and repair proteins, enzymatic processes of microorganisms including inhibitor design, as well as method design for improving the ability to crystallize difficult to handle proteins as seen with the nuclear receptors.