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Design of Cyclic Peptides That Bind Protein Surfaces with Antibody-Like Affinity

Millward, Steven W. and Fiacco, Stephen and Austin, Ryan J. and Roberts, Richard W. (2007) Design of Cyclic Peptides That Bind Protein Surfaces with Antibody-Like Affinity. ACS Chemical Biology, 2 (9). pp. 625-634. ISSN 1554-8929. PMCID PMC3747972. https://resolver.caltech.edu/CaltechAUTHORS:20170201-135420400

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Abstract

There is a pressing need for new molecular tools to target protein surfaces with high affinity and specificity. Here, we describe cyclic messenger RNA display with a trillion-member covalent peptide macrocycle library. Using this library, we have designed a number of high-affinity, redox-insensitive, cyclic peptides that target the signaling protein Gαi1. In addition to cyclization, our library construction took advantage of an expanded genetic code, utilizing nonsense suppression to insert N-methylphenylalanine as a 21st amino acid. The designed macrocycles exhibit several intriguing features. First, the core motif seen in all of the selected variants is the same and shares an identical context with respect to the macrocyclic scaffold, consistent with the idea that selection simultaneously optimizes both the cyclization chemistry and the structural placement of the binding epitope. Second, detailed characterization of one molecule, cyclic Gαi binding peptide (cycGiBP), demonstrates substantially enhanced proteolytic stability relative to that of the parent linear molecule. Third and perhaps most important, the cycGiBP peptide binds the target with very high affinity (K_i ≈ 2.1 nM), similar to those of many of the best monoclonal antibodies and higher than that of the βγ heterodimer, an endogenous Gαi1 ligand. Overall the work provides a general route to design novel, low-molecular-weight, high-affinity ligands that target protein surfaces.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/cb7001126DOIArticle
http://pubs.acs.org/doi/abs/10.1021/cb7001126PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747972/PubMed CentralArticle
ORCID:
AuthorORCID
Austin, Ryan J.0000-0002-5302-5266
Roberts, Richard W.0000-0002-8587-5097
Additional Information:© 2007 American Chemical Society. Received 20 May 2007. Date accepted 22 August 2007. Published online 21 September 2007. Published in print 1 September 2007. We would like to than S. Ross for his help with molecular characterization of the GiBPs and B. Ja for his helpful advice in all aspects of the project. We thank T. Takahashi for his advice and assistance with DNA sequencing and N. Zacharias for synthesis of pdCpA. This work was supported by National Institutes of Health (NIH) GM R01 60416 (R.W.R.), NIH R21 GM 76678 (R.W.R.), and the Charles Lee Powell Foundation.
Funders:
Funding AgencyGrant Number
NIHGM R01 60416
NIHR21 GM 76678
Charles Lee Powell FoundationUNSPECIFIED
Issue or Number:9
PubMed Central ID:PMC3747972
Record Number:CaltechAUTHORS:20170201-135420400
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170201-135420400
Official Citation:Design of Cyclic Peptides That Bind Protein Surfaces with Antibody-Like Affinity Steven W. Millward, Stephen Fiacco, Ryan J. Austin, and Richard W. Roberts ACS Chemical Biology 2007 2 (9), 625-634 DOI: 10.1021/cb7001126
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73943
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:02 Feb 2017 03:43
Last Modified:09 Mar 2020 13:19

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