Monday, March 15, 2010

Click chemistry builds molecular library for antituberculosis agents

The authors identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. They demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.

This is another good example that a small library, 80 in this case, built by click chemistry, yields an inhibitor with IC50 at 1.26 uM in a single selection round. Notably, the products were collected by simple centrifugation after 48 hr reaction, assessed by liquid chromatography–mass spectrometry to be at least 70–100% pure and used directly for screening without further purification.

Also, the effective strategy is used again here for the acquisition of active site-directed, potent, and selective PTP inhibitors  - tethering a nonhydrolyzable pTyr mimetic to an appropriately functionalized moiety in order to engage both the active site and a unique nearby subpocket. This strategy of utilising click chemistry has been reported a few times and proves to be productive.

PNAS, 2010, 4573.

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