FOR 2372:  G protein signalling cascades: with new molecular probes and modulators towards novel pharmacological concepts

• Subject Area: Medicine ; Biology ; Chemistry
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 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 Programme: Research Units
• International Connection: Denmark, Italy, Switzerland, USA

Projects

• Biosynthesis of the selective Gq protein inhibitor FR900359 in Chromobacterium vaccinii as basis for compound supply and structural modifications (Applicants Crüsemann, Max ;  König, Gabriele M. )
• Coordination Funds (Applicant Kostenis, Evi )
• Development and characterization of heterocyclized dipeptide derivatives as inhibitors for heterotrimeric G proteins (Applicant Gütschow, Michael )
• Effects of direct pharmacological Gq protein modulation on lung and right heart remodeling (Applicants Fleischmann, Bernd ;  Wenzel, Daniela )
• Gq/11-mediated GPCR signaling in melanoma pathogenesis and therapy (Applicants Gaffal, Evelyn ;  Tüting, Thomas )
• Impact of Gq signaling in the brown adipose tissue (Applicant Pfeifer, Alexander )
• Medicinal chemistry of Gq proteins and their inhibitors: synthesis, computational calculations and (bio)analytical studies (Applicant Müller, Christa E. )
• Pharmacological readdressing and mechanistic analysis of Gq activation (Applicant Kostenis, Evi )
• Resolving the mechanism of specific G-protein inhibitors by NMR spectroscopy (Applicant Glaubitz, Clemens )
• Revisiting long-held tenets in GPCR and G protein signal transduction with macrocyclic inhibitors of heterotrimeric Gq/11 proteins and state-of-the-art genome editing (Applicant Kostenis, Evi )
• Structural molecular pharmacology of G protein inhibitors. (Applicants Deupi, Xavier ;  Schertler, Gebhard )
• Synthesis and characterization of macrocyclic peptide inhibitors of the Galpha protein family (Applicant Imhof, Ph.D., Diana )
• Towards understanding structural and dynamical determinants of G protein inhibition - rational design of novel subtype specific G-protein inhibitors (Applicant Tietze, Daniel )

• Spokesperson: Professorin Dr. Evi Kostenis