Peptide Bicycles that Inhibit the Grb2 SH2 Domain.
Kritzer, Joshua A.
- Developing short peptides into useful probes and therapeutic leads remains a difficult challenge. Structural rigidification is a proven method for improving the properties of short peptides. In this work, we report a strategy for stabilizing peptide macrocycles by introducing side-chain-to-side-chain staples to produce peptide bicycles with higher affinity, selectivity, and resistance to degradati... read moreon. We have applied this strategy to G1, an 11-residue peptide macrocycle that binds the Src homology 2 (SH2) domain of growth-factor-bound protein 2 (Grb2) Several homodetic peptide bicycles were synthesized entirely on-resin with high yields. Two rounds of iterative design produced peptide bicycle BC1, which is 60 times more potent than G1 and 200 times more selective. Moreover, BC1 is completely intact after 24 hours in buffered human serum, conditions under which G1 is completely degraded. Our peptide-bicycle approach holds promise for the development of selective inhibitors of SH2 domains and other phosophotyrosine (pTyr)-binding proteins, as well as inhibitors of many other protein-protein interactions. This is the peer reviewed version of the following article: Quartararo, J. S., Wu, P. and Kritzer, J. A. (2012), Peptide Bicycles that Inhibit the Grb2 SH2 Domain. ChemBioChem, 13: 1490-1496, which has been published in final form at doi:10.1002/cbic.201200175. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.read less
- Quartararo, J. S., Wu, P. and Kritzer, J. A. (2012), Peptide Bicycles that Inhibit the Grb2 SH2 Domain. ChemBioChem, 13: 1490-1496. doi:10.1002/cbic.201200175.