Utilization of peptide phage display to investigate hotspots on IL-17A and what it means for drug discovery.

Joey P Ting,Sepideh Afshar,Danalyn Manglicmot,Feiyu F Zhang,Jeffrey A Dodge,Jordi Benach,Aiping Zhang,Christopher Groshong,Michael E Woodman,Stephen Antonysamy,Spencer B Jones,Michael J Chalmers,Howard Broughton,Alfonso Espada,Marijane Russell,Frances Tung,Holly A Bina,Stephen Wasserman,Alexander Wlodawer

doi:10.1371/journal.pone.0190850

Joey P Ting, Sepideh Afshar + Show 17 more

Open Access

https://doi.org/10.1371/journal.pone.0190850

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Abstract

To date, IL-17A antibodies remain the only therapeutic approach to correct the abnormal activation of the IL-17A/IL-17R signaling complex. Why is it that despite the remarkable success of IL-17 antibodies, there is no small molecule antagonist of IL-17A in the clinic? Here we offer a unique approach to address this question. In order to understand the interaction of IL-17A with its receptor, we combined peptide discovery using phage display with HDX, crystallography, and functional assays to map and characterize hot regions that contribute to most of the energetics of the IL-17A/IL-17R interaction. These functional maps are proposed to serve as a guide to aid in the development of small molecules that bind to IL-17A and block its interaction with IL-17RA.

Highlights

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that plays a key role in host defense and inflammation
IL-17A belongs to a family of proteins that constitute protein-protein interaction (PPI) targets
Like other members of the PPI family, the interface between IL-17A and its receptor is broad, flat, and largely devoid of grooves that are suitable for binding traditional small molecules

Summary

Introduction

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that plays a key role in host defense and inflammation. Binding of IL-17A to a heteromeric receptor complex stimulates various signal transduction pathways such as NF-κb and AP-1 [5]. This triggers up-regulation of matrix metalloproteinases and various pro-inflammatory cytokines and chemokines including IL-1, IL-6, GM-CSF, CXCL-1, CCL2, and CCL7. Immune cells, including neutrophils and monocytes, are attracted to the inflammation site. Elevated levels of IL-17A and the resulting cytokine release are linked to many autoimmune related diseases, including psoriasis, asthma, and rheumatoid arthritis [1,2,3,4, 6]

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