Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors

作者：Lee Sang Yong; Sarkar Soumya; Bhattarai Sanjay; Namasivayam Vigneshwaran; De Jonghe Steven; Stephan Holger; Herdewijn Piet; El Tayeb Ali; Mueller Christa E

来源：Frontiers in Pharmacology, 2017, 8: 54.

DOI：10.3389/fphar.2017.00054

• ectonucleotidase inhibitors
• enzyme assay
• p-nitrophenyl 5 '-thymidine monophosphate
• NPP1
• NPP1 inhibitors
• nucleotide pyrophosphatase 1

Nucleotide pyrophosphatase/phosphodiesterase type 1 (NPP1) is a membrane glycoprotein involved in the hydrolysis of extracellular nucleotides. Its major substrate is ATP which is converted to AMP and diphosphate. NPP1 was proposed as a new therapeutic target in brain cancer and immuno-oncology. Several NPP1 inhibitors have been reported to date, most of which were evaluated vs. the artificial substrate p-nitrophenyl 5'-thymidine monophosphate (p-Nph-5'-TMP). Recently, we observed large discrepancies in inhibitory potencies for a class of competitive NPP1 inhibitors when tested vs. the artificial substrate p-Nph-5'-TMP as compared to the natural substrate ATP. Therefore, the goal of the present study was to investigate whether inhibitors of human NPP1 generally display substrate-dependent inhibitory potency. Systematic evaluation of nucleotidic as well as non-nucleotidic NPP1 inhibitors revealed significant differences in determined K-i values for competitive, but not for non-and un-competitive inhibitors when tested vs. the frequently used artificial substrate p-Nph-5'-TMP as compared to ATP. Allosteric modulation of NPP1 by p-Nph-5'-TMP may explain these discrepancies. Results obtained using the AMP derivative p-nitrophenyl 5'-adenosine monophosphate (p-Nph-5'-AMP) as an alternative artificial substrate correlated much better with those employing the natural substrate ATP.

• 出版日期2017-2-15
• 单位河北医科大学