A11: SFB 1328

A11 Project movie

A11: Summary

This project is aimed at developing potent, selective modulators of the ATP-hydrolyzing ecto-enzymes CD39 and NPP1. The extracellular domain of the human CD39, recombinantly expressed in Sf9 insect cells, will be co-crystallized with modulators that were developed in the first funding period. Structural information will allow further, targeted optimization of ortho- and allosteric modulators. Fluorophore-labeled modulators and photoactivatable prodrugs will be synthesized as biological tools. Selected modulators and labeled compounds will be synthesized in large scale to allow in vitro and in vivo studies by collaboration partners in models of inflammation and immunity.

Prof. Dr. Christa E. Müller

E-Mail: christa.mueller©uni-bonn.de
www: Pharmaceutical Institute & PharmaCenter Bonn, University of Bonn

Selected publications (*equal contribution)

Breidenbach J, Lemke C, Pillaiyar T, Schäkel L, Al Hamwi G, Diett M, Gedschold R, Geiger N, Lopez V, Mirza S, Namasivayam V, Schiedel AC, Sylvester K, Thimm D, Vielmuth C, Phuong Vu L, Zyulina M, Bodem J, Gütschow M, Müller CE (2021) Targeting the main protease of SARS-CoV-2: From the establishment of high throughput screening to the design of tailored inhibitors. Angew Chem Int Ed Engl 60:10423-10429
Tian M, Abdelrahman A, Baqi Y, Fuentes E, Azazna D, Spanier C, Densborn S, Hinz S, Schmid R, Müller CE (2020) Discovery and structure-activity relationships of salicylanilide derivatives as potent, non-acidic P2X1 receptor antagonists. J Med Chem 63:6164-6178.
Jiang J, Seel CJ, Temirak A, Namasivayam V, Arridu A, Schabikowski J, Baqi Y, Hinz S, Hockemeyer J, Müller CE (2019) A_2B adenosine receptor antagonists with picomolar potency. J Med Chem 62:4032-4055.
Claff T, Yu J, Blais V, Patel N, Martin C, Wu L, Han GW, Holleran BJ, Van der Poorten O, White KL, Hanson MA, Sarret P, Gendron L, Cherezov V, Katritch V, Ballet S, Liu ZJ, Müller CE,* Stevens RC* (2019) Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists. Sci Adv 5:eaax9115
Bhattarai S, Freundlieb M, Pippel J, Meyer A, Abdelrahman A, Fiene A, Lee SY, Zimmermann H, Yegutkin GG, Sträter N, El-Tayeb A, Müller CE (2015) a ,β-Methylene-ADP (AOPCP) derivatives and analogues: development of potent and selective ecto-5’-nucleotidase (CD73) inhibitors. J Med Chem 58:6248-6263.
Zhang K, Zhang J, Gao ZG, Zhang D, Zhu L, Han GW, Moss SM, Paoletta S, Kiselev E, Lu W, Fenalti G, Zhang W, Müller CE, Yang H, Jiang H, Cherezov V, Katritch V, Jacobson KA, Stevens RC, Wu B, Zhao Q (2014) Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature 509:115-118.
Zhang J, Zhang K, Gao ZG, Paoletta S, Zhang D, Han GW, Li T, Ma L, Zhang W, Müller CE, Yang H, Jiang H, Cherezov V, Katritch V, Jacobson KA, Stevens RC, Wu B, Zhao Q (2014) Agonist-bound structure of the human P2Y12 receptor. Nature 509:119-122.
Gnad T, Scheibler S, von Kügelgen I, Scheele C, Kilic A, Glode A, Hoffmann LS, Reverte-Salisa L, Horn P, Mutlu S, El-Tayeb A, Kranz M, Deuther-Conrad W, Brust P, Lidell ME, Betz MJ, Enerback S, Schrader J, Yegutkin GG, Müller CE, Pfeifer A (2014) Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516:395-399.
Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Müller CE (2011) Nomenclature and classification of adenosine receptors – An update. Pharmacol Rev 63:1-34
Baqi Y, Müller CE (2010) Synthesis of alkyl- and aryl-amino-substituted anthraquinone derivatives by microwave-assisted copper(0)-catalyzed Ullmann coupling reactions. Nature Protoc 5:945-953.