G-Protein Modulators

G protein coupled receptors (GPCRs) are important target molecules for drugs, as they are responsible for a multitude of biological responses (e.g. cell proliferation and differentiation) and are involved in the development of numerous diseases. Many of these reactions and the associated signal transduction processes are controlled by the binding of G proteins to the intracellular side of the receptor. These are proteins that can bind guanine nucleotide diphosphate (GDP, inactive) or guanine nucleotide triphosphate (GTP, active) depending on their activity state. Incorrect signal transduction by G proteins can be important for the development of diseases.

Thus, G proteins are attractive targets for the development of pharmacologically interesting tools that can be used for a better understanding of the effects of G proteins and the consequences of their signal transduction pathways. The use of peptides as modulators of G proteins may serve as a strategy which combines the advantages of small molecules, such as cheaper and easier synthesis and cell penetration capability, with the advantages of large molecules, such as selectivity and specificity. One of the few compounds used as potent and specific Gαq protein modulator is the depsipeptide FR900359 ^[1-3]. For other Gα subunits, however, there is great interest in developing specific and selective modulators, too ^[1].

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Fig. 1: G protein-mediated signal transduction: After extracellular binding of the ligand to the GPCR, the heterotrimeric G protein dissociates into the Gα and Gβγ subunits, which can influence downstream effectors [1]. © Pharmazeutische Biochemie und Bioanalytik

[1] Reher, R., Kühl, T., Annala, S., Benkel, T., Kaufmann, D., Nubbemeyer, B., Odhiambo, J. P., Heimer, P., Bäuml, C. A., Kehraus, S., Crüsemann, M., Kostenis, E., Tietze, D., König, G. M., Imhof, D., ChemMedChem 13 (2018) 1634-1643.

[2] Schrage, R., Schmitz, A. L., Gaffal, E., Annala, S., Kehraus, S., Wenzel, D., Büllesbach, K. M., Bald, T., Inoue, A., Shinjo, Y., Galandrin, S., Shridhar, N., Hesse, M., Grundmann, M., Merten, N., Charpentier, T. H., Martz, M., Butcher, A. J., Slodczyk, T., Armando, S., Effern, M., Namkung, Y., Jenkins, L., Horn, V., Stößel, A., Dargatz, H., Tietze, D., Imhof, D., Gales, C., Drewke, C., Müller, C. E., Hölzel, M., Milligan, G., Tobin, A. B., Gomeza, J., Dohlman, H. G., Sondek, J., Harden, T. K., Bouvier, M., Laporte, S. A., Aoki, J., Fleischmann, B. K., Mohr, K., König, G. M., Tüting, T., Kostenis, E., Nat. Commun. 6 (2015) 1-17.

[3] Schmitz, A.-L., Schrage, R., Gaffal, E., Charpentier, T. H., Wiest, J., Hiltensperger, G., Morschel, J., Hennen, S., Häußler, D., Horn, V., Wenzel, D., Grundmann, M., Büllesbach, K. M., Schröder, R., Brewitz, H. H., Schmidt, J., Gomeza, J., Galés, C., Fleischmann, B. K., Tüting, T., Imhof, D., Tietze, D., Gütschow, M., Holzgrabe, U., Sondek, J., Harden, T. K., Mohr, K., Kostenis, K., Chem. Biol. 21 (2014) 890-902.