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A General Synthetic Approach for Designing Epitope Targeted Macrocyclic Peptide Ligands

Das, Samir and Nag, Arundhati and Liang, JingXin and Bunck, David N. and Umeda, Aiko and Farrow, Blake and Coppock, Matthew B. and Sarkes, Deborah A. and Finch, Amethist S. and Agnew, Heather D. and Pitram, Suresh and Lai, Bert and Yu, Mary Beth and Museth, A. Katrine and Deyle, Kaycie M. and Lepe, Bianca and Rodriguez-Rivera, Frances P. and McCarthy, Amy and Alvarez-Villalonga, Belen and Chen, Ann and Heath, John and Stratis-Cullum, Dimitra N. and Heath, James R. (2015) A General Synthetic Approach for Designing Epitope Targeted Macrocyclic Peptide Ligands. Angewandte Chemie International Edition, 54 (45). pp. 13219-13224. ISSN 1433-7851. PMCID PMC4890538. https://resolver.caltech.edu/CaltechAUTHORS:20150921-111839917

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Abstract

We describe a general synthetic strategy for developing high-affinity peptide binders against specific epitopes of challenging protein biomarkers. The epitope of interest is synthesized as a polypeptide, with a detection biotin tag and a strategically placed azide (or alkyne) presenting amino acid. This synthetic epitope (SynEp) is incubated with a library of complementary alkyne or azide presenting peptides. Library elements that bind the SynEp in the correct orientation undergo the Huisgen cycloaddition, and are covalently linked to the SynEp. Hit peptides are tested against the full-length protein to identify the best binder. We describe development of epitope-targeted linear or macrocycle peptide ligands against 12 different diagnostic or therapeutic analytes. The general epitope targeting capability for these low molecular weight synthetic ligands enables a range of therapeutic and diagnostic applications, similar to those of monoclonal antibodies.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1002/anie.201505243DOIArticle
http://onlinelibrary.wiley.com/doi/10.1002/anie.201505243/abstractPublisherArticle
http://onlinelibrary.wiley.com/doi/10.1002/anie.201505243/suppinfoPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890538/PubMed CentralArticle
ORCID:
AuthorORCID
Liang, JingXin0000-0001-6600-8409
Bunck, David N.0000-0002-6246-9846
Heath, James R.0000-0001-5356-4385
Additional Information:© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Received: June 8, 2015; Revised: August 12, 2015; Article first published online: 17 Sep. 2015. The various PCCs and methods reported here were developed under funding from the Bill and Melinda Gates Foundation, the Institute for Collaborative Biotechnologies (W911NF-09-0001) from the U.S. Army Research Office, the Defense Advanced Research Projects Agency (DARPA) through the Cooperative Agreement HR0011-11-2-0006, the Jean Perkins Foundation, and the National Cancer Institute through grant #1U54 CA199090-01 (JRH PI).
Funders:
Funding AgencyGrant Number
Bill and Melinda Gates FoundationUNSPECIFIED
Army Research Office (ARO)W911NF-09-0001
Defense Advanced Research Projects Agency (DARPA)HR0011-11-2-0006
Jean Perkins FoundationUNSPECIFIED
National Cancer Institute1U54 CA199090-01
Subject Keywords:click chemistry; combinatorial chemistry; macrocyclic ligands; metathesis; peptides
Issue or Number:45
PubMed Central ID:PMC4890538
Record Number:CaltechAUTHORS:20150921-111839917
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150921-111839917
Official Citation:Das, S., Nag, A., Liang, J., Bunck, D. N., Umeda, A., Farrow, B., Coppock, M. B., Sarkes, D. A., Finch, A. S., Agnew, H. D., Pitram, S., Lai, B., Yu, M. B., Museth, A. K., Deyle, K. M., Lepe, B., Rodriguez-Rivera, F. P., McCarthy, A., Alvarez-Villalonga, B., Chen, A., Heath, J., Stratis-Cullum, D. N. and Heath, J. R. (2015), A General Synthetic Approach for Designing Epitope Targeted Macrocyclic Peptide Ligands. Angew. Chem. Int. Ed., 54: 13219–13224. doi:10.1002/anie.201505243
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:60377
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Sep 2015 18:39
Last Modified:09 Mar 2020 13:19

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