Journal
ACS CHEMICAL BIOLOGY
Volume 8, Issue 2, Pages 297-302Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb3005403
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Funding
- Australian Research Council (ARC)
- National Health and Medical Research Council (NHMRC) [575561, 637360, 461221, 1016701]
- Leukemia and Lymphoma Society (LLS) [SCOR 7413]
- Australian Cancer Research Foundation
- NHMRC IRIISS grant [361646]
- Victorian State Government OIS grant
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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.
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