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FOR 2372:  G-Protein Signalkaskaden: mit neuen molekularen Sonden und Wirkstoffen zu neuen pharmakologischen Konzepten

Fachliche Zuordnung Medizin
Biologie
Chemie
Förderung Förderung von 2016 bis 2024
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 273251628
 
Traditionally, GPCRs rather than their associated G proteins were favored for drug development. This is because targeting of specific receptors holds great promise for the precise manipulation of physiology controlled by individual receptors. However, such an approach may fail, if pathology is complex involving 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 [10-15]. Consequently, our consortium will focus on two main lines of research that directly follow from these considerations:(i) better understand the role of G proteins under (patho-)physiological conditions(ii) exploit G proteins rather than their linked receptors as novel targets for therapeutic interventions with those diseases amenable to topical therapy.Both strategies would require modulators with selectivity for a given subfamily of G proteins. Currently, however, there are almost no G protein inhibitors available that are active in intact cells, on the level of an isolated organ or in the living organism.Goals. Our multi-disciplinary consortium aims at the rational design and the generation of novel, cell-permeable signaling inhibitors with selectivity for G protein families. We will generate new inhibitors by combining complementary chemical and biological approaches such as chemical synthesis starting from existing lead structures, as well as combinatorial peptide-, bio- and mutasynthesis. Molecular-mechanistic analyses, elucidation of the mode of action, and target structure-based rational optimization will be employed to identify those inhibitors that can be applied in cellular in vitro and ex vivo/in vivo models. This strategy will provide us with insight into the relevance of individual signaling cascades within complex signaling networks and (patho-)physiological events.As GPCRs serve as molecular targets for a plethora of drugs, we would expect that novel principles for piloting intracellular signaling might also inspire the development of therapies addressing GPCRs themselves.
DFG-Verfahren Forschungsgruppen
Internationaler Bezug Dänemark, Italien, Schweiz, USA

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