Chemical Tools for the Investigation of Phosphatases

• Applicant: Professorin Dr. Maja Köhn
• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2010 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 165935751

Phosphatases are enzymes that are involved in promoting a diverse set of diseases ranging from cancer through impaired function to bacteria-induced pathogenesis when they are of bacterial origin. The goal of this program is to design modulators and semisynthetic proteins and to apply them to study phosphatases that are actively promoting infection and cancer. One focus lies on phosphatases that interact with phosphatidylinositol phosphates, which are important signaling lipids. Proposed modulators will therefore be based on phosphatidylinositol phosphate structures. A novel approach to synthesize these compounds based on solid phase chemistry will be applied. In addition, I envision a new mode of action to inhibit membrane localization of the cancer-related phosphatase PRL-3 using these inhibitors. For protein tyrosine phosphatases, novel peptidic conformation-restrained inhibitors will be designed based on their natural substrate specificity. Finally, a new approach to find natural phosphatase substrates is envisioned, which will be based on expressed protein ligation and/or genetic encoding of unnatural amino acids. These tools will be applied in vitro and in vivo. The studies will contribute to the understanding of phosphatase regulation and signaling pathways as well as provide novel means to limit disease progression by phosphatases.

• DFG Programme: Independent Junior Research Groups