Project Details
Projekt
Coordination Funds
Applicant
Professorin Dr. Evi Kostenis
Subject Area
Pharmacy
Term
from 2016 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 273251628
GTP/GDP exchange and the intrinsic GTPase-activity of GTP binding proteins constitute widespread regulatory mechanisms in cells. These are utilized by heterotrimeric αβγ G proteins, downstream effectors of G protein-coupled receptors (GPCRs), to directly or indirectly regulate numerous physiological processes in mammals. Despite the discovery of G proteins almost 30 years ago and their relevance for maintaining homeostasis in response to various extracellular cues, remarkably little effort has been devoted to development of selective and cell permeable pharmacological agents for inhibition of members of this protein family. This is in stark contrast to the plethora of modulators currently available for pharmacological control of GPCRs, and likely relates to the fact that inhibition of receptor function rather than their shared signaling cascades is a more specific approach to interfere with pathologies. Yet, such an approach may fail, if pathology is complex and involves dysregulation of more than one receptor and its associated signaling circuitry as is the case in certain diseases of the lung, in metabolic disturbances, as well as certain forms of pain and cancer. Therefore, development of G protein-targeting pharmacological agents that are active in intact cells, on the level of an isolated organ or ideally also in the living organism would offer unique opportunities to explore the biological consequences that arise from more broad inhibition of signaling components.One such notable G protein inhibiting agent was recently introduced by our RU to the scientific community: FR900359 (FR). FR900359 (FR) is a macrocyclic depsipeptide with exceptional selectivity for inhibition of Gq-mediated signal transduction involving Gαq, Gα11, and Gα14 proteins. It is the core of our current RU2372, and was the only available Gq-specific inhibitor when we formed our consortium. Given its outstanding value as molecular probe to specifically interdict Gq signaling, our current efforts aim at (i) hypothesis-driven design and generation of novel, cell-permeable FR-scaffold-based inhibitors with selectivity for distinct G protein families, (ii) characterization of their mechanism of action including visualization of atomic details of inhibitor-target complexes, and (iii) application of existing and newly developed molecules to understand signaling principles on the level of G protein heterotrimers, their downstream effectors or their upstream activating receptors.We anticipate this strategy to provide us with insight into the relevance and contribution of individual signaling cascades within complex signaling networks in health and disease.
DFG Programme
Research Units
