Journal Article

PUBDB-2025-01465

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Synthesis, Characterization, Interactions, and Immunomodulatory Function of Ectonucleotidase CD39/CD73 Inhibitor 8-Butylthioadenosine 5′-Monophosphate

Bi, C. ; Mirza, S. ; Baburi, H. ; Schäkel, L. ; Winzer, R. ; Moschütz, S. ; Keetz, K. ; Lopez, V. ; Pelletier, J. ; Sévigny, J. ; Schulze zur Wiesch, J. ; Claff, T. ; Tolosa, E. ; Namasivayam, V. ; Straeter, N.Extern* ; Müller, C. E. (Corresponding author)

2025
ACS Publications Washington, DC

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Please use a persistent id in citations: doi:10.1021/acsptsci.5c00126

Abstract: Ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39) catalyzes the extracellular hydrolysis of ATP generating AMP, while ecto-5′-nucleotidase (CD73) further hydrolyzes AMP yielding immunosuppressive adenosine. 8-Butylthioadenosine 5′-monophosphate (8-BuS-AMP) was described as a CD39 inhibitor but has been poorly characterized. The standard CD39 antagonist ARL 67156 is not suitable for in vivo studies due to metabolic instability. In the present study, we optimized and upscaled the synthesis of 8-BuS-AMP and performed a comprehensive investigation of its properties. It behaves as a competitive inhibitor at human and mouse CD39, and additionally inhibits CD73. Docking studies using a homology model of human CD39 and determination of an atomic-resolution (1.06 Å) cocrystal structure with human CD73 indicated the inhibitor’s interactions within the substrate binding pockets and explained the compound’s stability toward hydrolysis. 8-BuS-AMP is metabolically highly stable in human and mouse liver microsomes. It inhibited ε-adenosine formation from ε-ATP and ε-AMP in human synovial fluid and enhanced activation and proliferation of peripheral human T lymphocytes. Thus, 8-BuS-AMP is a recommended tool compound for studying purinergic signaling in vitro and in vivo, being superior to the standard CD39 inhibitor ARL 67156. Moreover, it may serve as a lead structure to develop drugs for the immunotherapy of cancer.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project G:(GEPRIS)335447717 - SFB 1328: Adeninnukleotide in Immunität und Entzündung (335447717) (335447717)

Experiment(s):

1. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Emerging Sources Citation Index ; IF >= 5 ; JCR ; SCOPUS ; Web of Science Core Collection

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