A11

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.

Selected publications (*equal contribution)

 

  1. 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
  2. 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. 
  3. Jiang J, Seel CJ, Temirak A, Namasivayam V, Arridu A, Schabikowski J, Baqi Y, Hinz S, Hockemeyer J, Müller CE (2019) A2B adenosine receptor antagonists with picomolar potency. J Med Chem 62:4032-4055.
  4. 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
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Müller CE (2011) Nomenclature and classification of adenosine receptors – An update. Pharmacol Rev 63:1-34
  10. 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.

Our Team

Prof. Dr. Christa Müller

Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

Dr. Amelie Fiene


Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

Carolin Sabrina Pikullik

Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

Eugen Potaptschuk


Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

Tobias Claff


Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

Helay Baburi


Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

Mirza Salahuddin


Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

M.Sc. Chungyang Bi

Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

Alumni

Dr. Vigneshwaran Namasivayam

Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

Laura Schäkel

Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

M.Sc. Constanze Schmies

Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

Contact

University Medical Center Hamburg-Eppendorf 
Department of Biochemistry and Molecular Cell Biology 
Martinistrasse 52
20246 Hamburg

Scientific Coordinator

Dr. Björn-Philipp Diercks
Fon: +49  (0) 40 7410 54338
E-Mail: b.diercks©uke.de

Administration

Laura Mitsching
Fon: +49  (0) 40 7410 50301
E-Mail: l.mitsching©uke.de