A11

A11: Summary

Activation of CD39 may be a novel strategy to prevent (or modulate) inflammatory conditions. We plan to develop potent activators and inhibitors with high selectivity for CD39 versus other ectonucleotidases. The compounds’ properties will be studied in vitro based on test systems previously established by our group. Homology modeling, mutagenesis studies, the determination of co-crystal structures and virtual screening approaches will complement our efforts to develop CD39 modulators and to gain a detailed understanding of the molecular and catalytic properties of this enzyme. Developed tool compounds will be evaluated in collaboration with partners within the CRC in in vitro and in vivo studies in different models.

Selected publications

 

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. Thimm D, Funke M, Meyer A, Müller CE (2013) 6-Bromo-8-(4-[3H]methoxybenzamido)-4-oxo-4Hchromene-2-carboxylic Acid: a powerful tool for studying orphan G protein-coupled receptor GPR35. J Med Chem 56:7084-7099.
  6. Anne Stößel, Miriam Schlenk, Sonja Hinz, Petra Küppers, Jag Heer, Michael Gütschow, Müller CE (2013) Dual targeting of adenosine A2A receptors and monoamine oxidase B by 4H-3,1-benzothiazin4-ones. J Med Chem 56:4580-4596.
  7. Flögel U, Burghoff S, van Lent PL, Temme S, Galbarz L, Ding Z, El-Tayeb A, Huels S, Bonner F, Borg N, Jacoby C, Müller CE, van den Berg WB, Schrader J (2012) Selective activation of adenosine A2A receptors on immune cells by a CD73-dependent prodrug suppresses joint inflammation in experimental rheumatoid arthritis. Sci Transl Med 4:146ra108.
  8. Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Müller CE (2011) Nomenclature and classification of adenosine receptors – An update. Pharmacol Rev 63:1-34.
  9. 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.
  10. Borrmann T, Hinz S, Bertarelli DC, Li W, Florin NC, Scheiff AB, Müller CE (2009) 1-alkyl-8(piperazine-1-sulfonyl)phenylxanthines: development and characterization of adenosine A2B receptor antagonists and a new radioligand with subnanomolar affinity and subtype specificity. J Med Chem 52:3994-4006.

Our Team

Prof. Dr. Christa Müller

Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

Dr. Vigneshwaran Namasivayam

Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

M.Sc. Constanze Schmies

Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

Laura Schäkel

Pharmaceutical Institute & Pharma Center Bonn

University of Bonn

M.Sc. Chungyang Bi

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