Activation of Apoptosis in Vivo by a Hydrocarbon-stapled BH3 Helix

Overview

Journal Science

Specialty Science

Date 2004 Sep 9

PMID 15353804

Citations 486

Authors

Loren D Walensky

Andrew L Kung

Iris Escher

Thomas J Malia

Scott Barbuto

Renee D Wright

Gerhard Wagner

Gregory L Verdine

Stanley J Korsmeyer

Affiliations

Soon will be listed here.

Abstract

BCL-2 family proteins constitute a critical control point for the regulation of apoptosis. Protein interaction between BCL-2 members is a prominent mechanism of control and is mediated through the amphipathic alpha-helical BH3 segment, an essential death domain. We used a chemical strategy, termed hydrocarbon stapling, to generate BH3 peptides with improved pharmacologic properties. The stapled peptides, called "stabilized alpha-helix of BCL-2 domains" (SAHBs), proved to be helical, protease-resistant, and cell-permeable molecules that bound with increased affinity to multidomain BCL-2 member pockets. A SAHB of the BH3 domain from the BID protein specifically activated the apoptotic pathway to kill leukemia cells. In addition, SAHB effectively inhibited the growth of human leukemia xenografts in vivo. Hydrocarbon stapling of native peptides may provide a useful strategy for experimental and therapeutic modulation of protein-protein interactions in many signaling pathways.

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