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Web Date: May 29, 2014

Chemists Report Potent Inhibitors Of Little-Studied Arthritis Enzyme

Medicinal Chemistry: ATP analogs could serve as drug leads for pseudogout
Department: Science & Technology | Collection: Life Sciences
News Channels: Biological SCENE, Organic SCENE
Keywords: pyrophosphatase, NPP1, ATP, AMP, pseudogout, diabetes, arthritis
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ATP Mimic
Researchers designed adenosine triphosphate (ATP) derivatives like this one to block the activity of the ATP-cleaving enzyme NPP1. The methylene group between two of the phosphates stymies the enzyme’s phosphate-cleaving machinery.
Credit: Hanoch Senderowitz
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ATP Mimic
Researchers designed adenosine triphosphate (ATP) derivatives like this one to block the activity of the ATP-cleaving enzyme NPP1. The methylene group between two of the phosphates stymies the enzyme’s phosphate-cleaving machinery.
Credit: Hanoch Senderowitz

For elderly patients with a form of arthritis called pseudogout, there are no treatment options that attack the underlying cause of the painful condition. Recently, scientists implicated increased activity from a little-known enzyme called NPP1 in the disease, and suspect that NPP1 also may play a role in other diseases, including diabetes. Now, researchers unveil the most potent NPP1 inhibitors to date, which could serve as starting points for pseudogout drug candidates (J. Med. Chem. 2014, DOI: 10.1021/jm500196c).

The enzyme, nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1), breaks adenosine triphosphate (ATP) into adenosine monophosphate and pyrophosphate, which is an essential step in bone formation. When NPP1 becomes overactive, it floods the extracellular space with pyrophosphate. This contributes to crystallization of calcium pyrophosphate in cartilage, triggering sudden, painful arthritic attacks. Some NPP1 inhibitors have been reported, but their potency is low.

The new NPP1 inhibitors were found by Bilha Fischer and Hanoch Senderowitz at Bar-Ilan University, in Israel; Jean Sévigny at Laval University, in Quebec; and their coworkers while they were designing ATP mimics as inhibitors of other ATP-cleaving enzymes. Some of these mimics had a methylene group in place of an oxygen linking the molecules’ phosphate groups. When the molecules bind to the enzymes, the methylene blocks the enzymes’ phosphate-cleaving machinery.

The team realized they had found some ATP analogs specific and potent against NPP1. In fact, the best-performing molecule inhibited NPP1 at nanomolar concentrations. Previous inhibitors worked only in the micromolar range.

Sévigny says these inhibitors could help scientists better understand how out-of-control NPP1 leads to crystal deposition in joints.

 
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