title: 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.
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: Samir
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: Arundhati
authors.initials: A
authors.lastname: Nag
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: JingXin
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: David N
authors.initials: DN
authors.lastname: Bunck
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: Aiko
authors.initials: A
authors.lastname: Umeda
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: Blake
authors.initials: B
authors.lastname: Farrow
authors.affiliation: Biotechnology Branch, Sensors & Electronic Devices Directorate, U.S. Army Research Laboratory, 2800 Powder Mill Road, Adelphi, MD 20783 (USA).
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Coppock
authors.affiliation: Biotechnology Branch, Sensors & Electronic Devices Directorate, U.S. Army Research Laboratory, 2800 Powder Mill Road, Adelphi, MD 20783 (USA).
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Sarkes
authors.affiliation: Biotechnology Branch, Sensors & Electronic Devices Directorate, U.S. Army Research Laboratory, 2800 Powder Mill Road, Adelphi, MD 20783 (USA).
authors.forename: Amethist S
authors.initials: AS
authors.lastname: Finch
authors.affiliation: Indi Molecular, 6162 Bristol Parkway, Culver City, CA 90230 (USA).
authors.forename: Heather D
authors.initials: HD
authors.lastname: Agnew
authors.affiliation: Indi Molecular, 6162 Bristol Parkway, Culver City, CA 90230 (USA).
authors.forename: Suresh
authors.initials: S
authors.lastname: Pitram
authors.affiliation: Indi Molecular, 6162 Bristol Parkway, Culver City, CA 90230 (USA).
authors.forename: Bert
authors.initials: B
authors.lastname: Lai
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Yu
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: A Katrine
authors.initials: AK
authors.lastname: Museth
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: Kaycie M
authors.initials: KM
authors.lastname: Deyle
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: Bianca
authors.initials: B
authors.lastname: Lepe
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: Frances P
authors.initials: FP
authors.lastname: Rodriguez-Rivera
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: Amy
authors.initials: A
authors.lastname: McCarthy
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: Belen
authors.initials: B
authors.lastname: Alvarez-Villalonga
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: Ann
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA).
authors.forename: John
authors.initials: J
authors.lastname: Heath
authors.affiliation: Biotechnology Branch, Sensors & Electronic Devices Directorate, U.S. Army Research Laboratory, 2800 Powder Mill Road, Adelphi, MD 20783 (USA).
authors.forename: Dimitra N
authors.initials: DN
authors.lastname: Stratis-Cullum
authors.affiliation: Department of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125 (USA). heath@caltech.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Heath
mesh_terms: D015195:Drug Design; D000939:Epitopes / Q000737:chemistry*; D008024:Ligands; D008970:Molecular Weight; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D000939:Epitopes; D008024:Ligands; D010456:Peptides, Cyclic; D011506:Proteins
keywords: click chemistry; combinatorial chemistry; macrocyclic ligands; metathesis; peptides