Applying novel approaches to develop new, more effective diabetes drugs
Project title: Pathways to a Cure: Novel, Innovative Insights into Insulin Signaling and Regulation using NMR Spectroscopy
Institution: University of Arizona
Pathway project publications: 5
Has delivered 16 invited lectures related to his Pathway Project
Major accomplishments:
We are undertaking an ambitious effort to comprehensively characterize two of the key regulators of the insulin pathway, called Protein-Tyrosine Phosphatase 1B (PTP1B) and Protein Phosphatase 1 (PP1) in order to identify potential new therapies for diabetes. To do this, we are using a combination of chemical proxies, enzyme assays and biophysics to study activity and inhibition which, together, are allowing us to understand how these enzymes achieve their full functionality. Unexpectedly, these discoveries are revealing completely novel approaches for inhibiting PTP1B and PP1 and new mechanisms by which inhibitors can target enzymes, both of which are critical for developing potent treatments for diabetes. These new data will not only greatly impact our ability to cure diabetes, but are key new discoveries for the fields of enzymology and biology in general.
Specifically, we have proven that small molecule inhibitors bind to intrinsically disordered regions (IDR) of proteins and alter the activity of a protein; i.e., this is precisely how the inhibitor MSI-1436 inhibits PTP1B activity. This is a key discovery as it is estimated that 30% of the proteome consists of IDRs. Most interestingly, we have also recently discovered that different time scales of motion are critical for PTP1B function and activity. Specifically, we carried out a tour-de-force experimental effort which showed that while slow motions drive PTP1B's active site chemistry, faster time scale motions allow for its allosteric regulation. This work is transforming our understanding of the role of protein motions in enzyme function. More importantly, these novel insights are now being leveraged for specific design of drugs to treat diabetes.
Impact statement:
My grandmother suffered from multiple complications of diabetes, including the loss of her feet, before she passed away. I think about this daily, as my mother and I are also both at risk. It is for this reason that I have combined my concern for diabetes with my long-standing interest in understanding how enzymes work. Namely, I study enzymes that play a central role in diabetes with the goal of making novel discoveries about how they function and then leveraging these data to develop novel cures for this disease. Enzymes can be inhibited using multiple routes. The most common is to block their active sites, comparable to throwing a wrench into an engine. This works well when the active site of the enzyme is unique; in this case highly selective molecules can be designed that fit in only to this site. The problem is that this does not work for many classes of enzymes because they often have similar active sites (i.e., have the same “engine”). Over the last decades, allosteric inhibitors have shown that they can overcome this problem as they bind outside the active site (i.e., outside the engine) in pockets that are unique. Our work funded by the Pathway award is focused on identifying these novel allosteric sites within essential enzymes that control the insulin signaling pathway. Critically, our studies are now allowing, for the first time, the rational design of specific allosteric inhibitors that will lead to completely novel treatments for this disease.
This work is having a profound impact on my career, as the science is impactful not only for diabetes but biology in general, and also on me personally, as I know that this work, along with that of other pathway awardees, will lead to a cure for this devastating disease.
