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Published November 2, 2015 | Accepted Version + Supplemental Material
Journal Article Open

A General Synthetic Approach for Designing Epitope Targeted Macrocyclic Peptide Ligands


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.

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).

Attached Files

Accepted Version - nihms787674.pdf

Supplemental Material - anie_201505243_sm_miscellaneous_information.pdf


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