Stabilizing the Pro-Apoptotic BimBH3 Helix (BimSAHB) Does Not Necessarily Enhance Affinity or Biological Activity
Details
Publication Year 2013-02, Volume 8, Issue #2, Page 297-302
Journal Title
ACS CHEMICAL BIOLOGY
Publication Type
Journal Article
Abstract
An attractive approach for developing therapeutic peptides is to enhance binding to their targets by stabilizing their a-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.
Publisher
AMER CHEMICAL SOC
Keywords
BCL-2 FAMILY PROTEINS; BH3 HELIX; PEPTIDE; BINDING; DEGRADATION; ACTIVATION; INHIBITOR; DOMAINS; ENERGY; BAX
WEHI Research Division(s)
Chemical Biology; Structural Biology
PubMed ID
23151250
Publisher's Version
https://doi.org/10.1021/cb3005403
Rights Notice
Copyright © 2013 American Chemical Society


Creation Date: 2013-02-01 12:00:00
Last Modified: 2016-01-12 09:53:15
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