Medicinal chemistry of Gq proteins and their inhibitors: synthesis, computational calculations and (bio)analytical studies
Team members
Jan Hendrik Voß, jvoss@uni-bonn.de
Jonathan Schlegel, jschlege@uni-bonn.de
Dr. Vignesh Namasivayam, vnamasiv@uni-bonn.de
Dr. Nader Boshta, nboshta@uni-bonn.de
Publications
Voss JH, Crüsemann M, Bartling CRO, Kehraus S, Inoue A, König GM, Strømgaard K, Müller CE. Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors. iScience. 2023 Mar 23;26(4):106492. doi: 10.1016/j.isci.2023.106492. PMID: 37091255; PMCID: PMC10119753.
Voss JH, Al-Hroub H, Gedschold R, Dietrich JM, Gaffal E, Toma M, Kehraus S, König GM, Brust P, Fleischmann BK, Wenzel D, Deuther-Conrad W, Müller CE. Imaging of Gαq Proteins in Mouse and Human Organs and Tissues. Pharmaceutics. 2022 Dec 24;15(1):57. doi: 10.3390/pharmaceutics15010057. PMID: 36678686; PMCID: PMC9865079.
Voss JH, Nagel J, Rafehi M, Guixà-González R, Malfacini D, Patt J, Kehraus S, Inoue A, König GM, Kostenis E, Deupi X, Namasivayam V, Müller CE. (2021) Unraveling binding mechanism and kinetics of macrocyclic Gαq protein inhibitors. Pharmacol Res. doi: 10.1016/j.phrs.2021.105880. Epub 2021 Sep 17. PMID: 34506902.
Schlegel JG, Tahoun M, Seidinger A, Voss JH, Kuschak M, Kehraus S, Schneider M, Matthey M, Fleischmann BK, König GM, Wenzel D, Müller CE. (2021) Macrocyclic Gq Protein Inhibitors FR900359 and/or YM-254890-Fit for Translation? ACS Pharmacol Transl Sci. doi: 10.1021/acsptsci.1c00021. PMID: 33860209; PMCID: PMC8033771.
Patt J, Alenfelder J, Pfeil EM, Voss JH, Merten N, Eryilmaz F, Heycke N, Rick U, Inoue A, Kehraus S, Deupi X, Müller CE, König GM, Crüsemann M, Kostenis E. (2021) An experimental strategy to probe Gq contribution to signal transduction in living cells. J Biol Chem. doi: https://doi.org/10.1016/j.jbc.2021.100472
Hermes C, Richarz R, Wirtz DA, Patt J, Hanke W, Kehraus S, Voß JH, Küppers J, Ohbayashi T, Namasivayam V, Alenfelder J, Inoue A, Mergaert P, Gütschow M, Müller CE, Kostenis E, König GM, Crüsemann M. (2021) Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359. Nat Commun. doi: 10.1038/s41467-020-20418-3.
Kuschak M, Schlegel JG, Schneider M, Kehraus S, Voss JH, Seidinger A, Matthey M, Wenzel D, Fleischmann BK, König GM, Müller CE. (2020) Sensitive LC-MS/MS Method for the Quantification of Macrocyclic Gαq Protein Inhibitors in Biological Samples. Front Chem. doi: 10.3389/fchem.2020.00833. PMID: 33173765; PMCID: PMC7540253.
Kuschak M, Namasivayam V, Rafehi M, Voss JH, Garg J, Schlegel JG, Abdelrahman A, Kehraus S, Reher R, Küppers J, Sylvester K, Hinz S, Matthey M, Wenzel D, Fleischmann BK, Pfeifer A, Inoue A, Gütschow M, König GM, Müller CE. (2020) Cell-permeable high-affinity tracers for Gq proteins provide structural insights, reveal distinct binding kinetics and identify small molecule inhibitors. Br J Pharmacol. doi: 10.1111/bph.14960. Epub 2020 Feb 11. PMID: 31881095; PMCID: PMC7070167.
Crüsemann M, Reher R, Schamari I, Brachmann AO, Ohbayashi T, Kuschak M, Malfacini D, Seidinger A, Pinto-Carbó M, Richarz R, Reuter T, Kehraus S, Hallab A, Attwood M, Schiöth HB, Mergaert P, Kikuchi Y, Schäberle TF, Kostenis E, Wenzel D, Müller CE, Piel J, Carlier A, Eberl L, Koenig GM (2017); Heterologous expression, biosynthetic studies and ecological function of the selective Gq-signaling inhibitor FR900359, Angew. Chem. Int. Ed., doi: 10.1002/anie.201707996
Matthey M, Roberts R, Seidinger A, Simon A, Schröder R, Kuschak M, Annala S, König GM, Müller CE, Hall IP, Kostenis E, Fleischmann BK, Wenzel D (2017); Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma, Sci Transl Med., 2, 407, doi:10.1126/scitranslmed.aag2288
Schrage R, Schmitz AL, Gaffal E, Annala S, Kehraus S, Wenzel D, Büllesbach KM, Bals T, Inoue A, Shinjo Y, Galandrin S, Shridhar N, Hesse M, Grundmann M, Merten N, Charpentier TH, Martz M, Butcher AJ, Slodczyk T, Armando S, Effer M, Namkung Y, Jenkins L, Horn V, Stößel A, Dargatz H, Tietze D, Imhof D, Galés C, Drewke C, Müller CE, Hölzel M, Milligan G, Tobin AB, Gomeza J, Dohlmann HG, Sondek J, Harden K, Bouvier M, Laporte SA, Aoki J, Fleischmann BK, Mohr K, König GM, Tüting T and Kostenis E (2015); The experimental power of FR900359 to study Gq-regulated biological processes, Nat Commun, 6, 10156, doi: 10.1038/ncomms10156