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Epitope-Targeted Macrocyclic Peptide Ligand with Picomolar Cooperative Binding to Interleukin-17F

Lai, Bert T. and Wilson, Jeré A. and Malette Loredo, Jacquie and Pitram, Suresh M. and LaBerge, Nicole A. and Heath, James R. and Agnew, Heather D. (2018) Epitope-Targeted Macrocyclic Peptide Ligand with Picomolar Cooperative Binding to Interleukin-17F. Chemistry: a European Journal, 24 (15). pp. 3760-3767. ISSN 0947-6539. doi:10.1002/chem.201704752.

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The IL-17 cytokine family is associated with multiple immune and autoimmune diseases and comprises important diagnostic and therapeutic targets. This work reports the development of epitope-targeted ligands designed for differential detection of human IL-17F and its closest homologue IL-17A. Non-overlapping and unique epitopes on IL-17F and IL-17A were identified by comparative sequence analysis of the two proteins. Synthetic variants of these epitopes were utilized as targets for in situ click screens against a comprehensive library of synthetic peptide macrocycles with 5-mer variable regions. Single generation screens yielded selective binders for IL-17F and IL-17A with low cross-reactivity. Macrocyclic peptide binders against two distinct IL-17F epitopes were coupled using variable length chemical linkers to explore the physical chemistry of cooperative binding. The optimized linker length yielded a picomolar affinity binder, while retaining high selectivity. The presented method provides a rational approach towards targeting discontinuous epitopes, similar to what is naturally achieved by many B cell receptors.

Item Type:Article
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URLURL TypeDescription
Heath, James R.0000-0001-5356-4385
Additional Information:© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Manuscript received: October 8, 2017; Accepted manuscript online: January 10, 2018; First published: 19 February 2018. This research was partially supported by the Institute for Collaborative Biotechnologies through grant W911NF‐09‐D‐0001 from the U.S. Army Research Office. We thank the Protein/Peptide Micro Analytical Laboratory at Caltech for Edman sequencing. The content of the information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. The Government had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Conflict of interest: J.R.H. is a founder and consultant/advisory board member of Indi Molecular, Inc.
Funding AgencyGrant Number
Army Research Office (ARO)W911NF-09-D-0001
Issue or Number:15
Record Number:CaltechAUTHORS:20180222-123456564
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Official Citation:B. T. Lai, J. A. Wilson, J. Malette Loredo, S. M. Pitram, N. A. LaBerge, J. R. Heath, H. D. Agnew, Chem. Eur. J. 2018, 24, 3760.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84923
Deposited By: Tony Diaz
Deposited On:22 Feb 2018 23:57
Last Modified:15 Nov 2021 20:24

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