A11

A11 Project movie

A11: Summary

Project A11 aims at altering the balance between pro-inflammatory ATP and anti-inflammatory ADO by novel modulators of CD39 activity. CD39 is a key enzyme in regulating the balance between ATP and ADO by converting ATP via ADP to AMP. CD39 was expressed, and complementary enzyme assays were established. Several competitive as well as allosteric modulators of CD39 were identified, synthesized and characterized. Potency, and/or metabolic stability was improved for three different classes of compounds: (i) ticlopidine derivatives, (ii) ARL67156 analogs, and (iii) 8-butylthio-AMP derivatives and analogs. However, selectivity was moderate due to additional inhibition of CD73 which converts AMP to ADO. Virtual screening and compound library screening was performed leading to the discovery of several structurally novel CD39 modulators. The synthesis of the best CD39 modulators, 8-methylamino-AMP and N6-(phenylbutyl)-8-methylamino-AMP (Ki 440 nM vs. membrane-bound CD39, 58 nM vs. soluble CD39), was upscaled for extended studies, and the compounds have been provided to collaborators within the CRC.

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. 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