Identification and Evaluation of Small Molecule Pan-caspase Inhibitors in Huntington's Disease Models

Overview

Journal Chem Biol

Publisher Elsevier

Specialties Biochemistry
Biology
Chemistry

Date 2010 Nov 25

PMID 21095569

Citations 30

Authors

Melissa J Leyva

Francesco DeGiacomo

Linda S Kaltenbach

Jennifer Holcomb

Ningzhe Zhang

Juliette Gafni

Hyunsun Park

Donald C Lo

Guy S Salvesen

Lisa M Ellerby

Jonathan A Ellman

Affiliations

Soon will be listed here.

Abstract

Huntington's Disease (HD) is characterized by a mutation in the huntingtin (Htt) gene encoding an expansion of glutamine repeats on the N terminus of the Htt protein. Numerous studies have identified Htt proteolysis as a critical pathological event in HD postmortem human tissue and mouse HD models, and proteases known as caspases have emerged as attractive HD therapeutic targets. We report the use of the substrate activity screening method against caspase-3 and -6 to identify three novel, pan-caspase inhibitors that block proteolysis of Htt at caspase-3 and -6 cleavage sites. In HD models these irreversible inhibitors suppressed Hdh(111Q/111Q)-mediated toxicity and rescued rat striatal and cortical neurons from cell death. In this study, the identified nonpeptidic caspase inhibitors were used to confirm the role of caspase-mediated Htt proteolysis in HD. These results further implicate caspases as promising targets for HD therapeutic development.

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