Polyoxometalates--potent and selective ecto-nucleotidase inhibitors

Area of Science:

• Inorganic Chemistry
• Biochemistry
• Pharmacology

Background:

• Polyoxometalates (POMs) are inorganic metal-oxygen cluster complexes with diverse biological activities.
• The molecular mechanisms underlying POM bioactivity, particularly their enzyme inhibition profiles, remain largely unexplored.
• Ecto-nucleotidases regulate purinergic signaling and are implicated in various physiological and pathological processes.

Purpose of the Study:

• To evaluate the inhibitory potential of various POMs and chalcogenide hexarhenium cluster complexes against a wide range of ecto-nucleotidases.
• To identify potent and selective inhibitors of specific ecto-nucleotidase families.

Main Methods:

• Screening of a series of polyoxometalates and chalcogenide hexarhenium cluster complexes.
• Enzyme inhibition assays to determine the potency (Ki values) and selectivity of POM compounds against human ecto-nucleotidases (NTPDases, NPPs, APs, eN).
• Determination of enzyme inhibition mechanisms (competitive, non-competitive).

Main Results:

• Discovery of [Co4(H2O)2(PW9O34)2](10-) (PSB-POM142) as the most potent inhibitor of human NTPDase1 (Ki: 3.88 nM).
• Identification of [TiW11CoO40](8-) (PSB-POM141, Ki: 1.46 nM) and [NaSb9W21O86](18-) (PSB-POM143, Ki: 4.98 nM) as highly potent and selective inhibitors of human NPP1.
• [NaP5W30O110](14-) (PSB-POM144) demonstrated broad inhibition against NTPDase1-3 and NPP1, acting as a potential pan-inhibitor.

Conclusions:

• This study reveals novel polyoxometalates as highly potent and selective inhibitors of key ecto-nucleotidases.
• The identified POMs represent valuable chemical tools for dissecting purinergic signaling pathways.
• Further in vivo investigations are warranted to explore the therapeutic potential of these promising POM inhibitors.