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Self-assembling Small Molecules Form Nanofibrils That Bind procaspase-3 to Promote Activation

Self-assembling Small Molecules Form Nanofibrils That Bind procaspase-3 to Promote Activation

Julie A Zorn, Holger Wille, Dennis W Wolan, James A Wells

J Am Chem Soc. 2011 Dec 14;133(49):19630-3.

PMID: 22066605

Abstract:

Modulating enzyme function with small-molecule activators, as opposed to inhibitors, offers new opportunities for drug discovery and allosteric regulation. We previously identified a compound, called 1541, from a high-throughput screen (HTS) that stimulates activation of a proenzyme, procaspase-3, to generate mature caspase-3. Here we further investigate the mechanism of activation and report the surprising finding that 1541 self-assembles into nanofibrils exceeding 1 μm in length. These particles are an unanticipated outcome from an HTS that have properties distinct from standard globular protein aggregators. Moreover, 1541 nanofibrils function as a unique biocatalytic material that activates procaspase-3 via induced proximity. These studies demonstrate a novel approach for proenzyme activation through binding to fibrils, which may mimic how procaspases are naturally processed on protein scaffolds.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42415319	Caspase Modulator I, 1541			Price

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