Peti also plans to work with fellow Brown biologist Marc Tatar to take the ideas into the fruit fly where they can investigate the differences made by known genetic mutations.
Another target is an enzyme called PTP1B, which can shut off insulin signaling. Because the goal in treating type 2 diabetes is to improve insulin function, Peti wants to stop PTP1B.
PTP1B has proven time and again to be tough to block without unintended consequences, but Peti hopes a less direct approach than others have taken will make a difference. Rather than targeting the main catalytic parts of the enzyme directly, he's looking at the behavior of a more peripheral but nevertheless influential structure called the "c-terminal segment." It's an underexplored region that could be targeted very specifically, likely with a combination of surgical strikes on more than one area. A key requirement of any drug is that it only affects insulin signaling and not other interactions by similar enzymes.
Sure enough, along with colleague Nicholas Tonks at the Cold Spring Harbor Laboratory, Peti has begun to characterize a drug that works in this area. They plan to use NMR to improve the understanding of the drug's workings further and use that knowledge to improve its abilities.
Peti's third approach under the ADA award is more traditional in that it depends "simply" on characterizing the structure of a complex of proteins, together known as GM:PP1. That complex controls the balance between storing glucose in the form of a larger "glycogen" molecule and breaking glycogen down into glucose. GM:PP1 accomplishes the latter by turning on an enzyme called glycogen phosphorylase.
Peti's idea is to figure out how a drug could inhibit GM:PP1's recognition of glycogen phosphorylase so that it doesn't break down glycogen into glucose so readily. Peti already knows where he wants to look on the proteins to try the idea and has developed a means of scree
|Contact: David Orenstein|