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Native Metabolomics for the Discovery of New Gx protein modulators

The cyclic depsipeptide FR900359 (FR), derived from the Traditional Chinese Medicine plant Ardisia crenata, selectively and highly potently inhibits Gαq/11/14 proteins and consequently signal transduction of Gq protein-coupled receptors, which are involved in pleiotropic physiological and pathophysiological processes. Therefore, FR has an exceptionally high value as a tool for pharmacological research. Currently, there are no known small molecule inhibitors for Gαs and Gα16 proteins

In order to accelerate the search for new potent modulators and to search more specifically and intelligently for the needle in the haystack, we are striving to establish new methods. Recently, together with Dr. Daniel Petras (Functional Metabolomics lab), we developed a native metabolomics approach (https://www.nature.com/articles/s41467-022-32016-6), which examines hundreds of compounds in a crude natural product extract for interactions with a target protein within 10 minutes.

 In a follow-up study with the Functional Metabolomics lab, we will now try to find new G protein inhibitors from various organisms via native metabolomics. In that way identified potentially new binders will then be analyzed by computer-assisted programs like GNPS and the SIRIUS framework with its integrated functions like CSI:FingerID or CANOPUS for fast dereplication of known natural products as well as classification and substructure analysis of potentially new G protein inhibitors. Afterwards the isolated new binder will be characterized biochemically via nanoDSF, GTPase Turnover, HDX-MS measurements.

This project is inverstigated by Amira Naimi