Stabilizing the pro-apoptotic BimBH3 helix (BimSAHB) does not necessarily enhance affinity or biological activity.

Abstract:

:An attractive approach for developing therapeutic peptides is to enhance binding to their targets by stabilizing their α-helical conformation, for example, stabilized BimBH3 peptides (BimSAHB) designed to induce apoptosis. Unexpectedly, we found that such modified peptides have reduced affinity for their targets, the pro-survival Bcl-2 proteins. We attribute this loss in affinity to disruption of a network of stabilizing intramolecular interactions present in the bound state of the native peptide. Altering this network may compromise binding affinity, as in the case of the BimBH3 stapled peptide studied here. Moreover, cells exposed to these peptides do not readily undergo apoptosis, strongly indicating that BimSAHB is not inherently cell permeable.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Okamoto T,Zobel K,Fedorova A,Quan C,Yang H,Fairbrother WJ,Huang DC,Smith BJ,Deshayes K,Czabotar PE

doi

10.1021/cb3005403

subject

Has Abstract

pub_date

2013-02-15 00:00:00

pages

297-302

issue

2

eissn

1554-8929

issn

1554-8937

journal_volume

8

pub_type

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