A General Synthetic Approach for Designing Epitope Targeted Macrocyclic Peptide Ligands
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 17, 2015
- Source ID
- 10.1002/anie.201505243
Entities
People
- A. Katrine Museth
- Aiko Umeda
- Amethist S. Finch
- Amy Mccarthy
- Ann Chen
- Arundhati Nag
- Belen Alvarez‐villalonga
- Bert Lai
- Bianca Lepe
- Blake Farrow
- David N Bunck
- Deborah A. Sarkes
- Dimitra N. Stratis‐cullum
- Frances P. Rodriguez‐rivera
- Heather D Agnew
- James R. Heath
- JingXin Liang
- John E. Heath
- Kaycie M. Deyle
- Mary Beth Yu
- Matthew B. Coppock
- Samir Das
- Suresh Pitram
Organizations
- Army Research Office
- Defense Advanced Research Projects Agency
- Gates Foundation
- Jean Perkins Foundation
- National Cancer Institute