Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site

Anti-IL17A therapies have proven effective for numerous inflammatory diseases including psoriasis, axial spondylitis and psoriatic arthritis. Modulating and/or antagonizing protein–protein interactions of IL17A cytokine binding to its cell surface receptors with oral therapies offers the promise to...

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Bibliographic Details
Published in:	Scientific reports Vol. 12; no. 1; p. 14561
Main Authors:	Goedken, Eric R., Argiriadi, Maria A., Dietrich, Justin D., Petros, Andrew M., Krishnan, Navasona, Panchal, Sanjay C., Qiu, Wei, Wu, Haihong, Zhu, Haizhong, Adams, Ashley M., Bodelle, Pierre M., Goguen, Lucas, Richardson, Paul L., Slivka, Peter F., Srikumaran, Myron, Upadhyay, Anup K., Wu, Bainan, Judge, Russell A., Vasudevan, Anil, Gopalakrishnan, Sujatha M., Cox, Philip B., Stoll, Vincent S., Sun, Chaohong
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 26-08-2022 Nature Publishing Group Nature Portfolio
Subjects:	631/154 631/154/1435 631/154/309 631/250/256 631/45/127 631/45/535/1266 631/45/535/878 Affinity Arthritis Cell surface Cytokines Drug development Humanities and Social Sciences Inflammatory diseases multidisciplinary NMR Nuclear magnetic resonance Protein interaction Psoriasis Psoriatic arthritis Science Science (multidisciplinary) Skin diseases Spondylitis
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Summary:	Anti-IL17A therapies have proven effective for numerous inflammatory diseases including psoriasis, axial spondylitis and psoriatic arthritis. Modulating and/or antagonizing protein–protein interactions of IL17A cytokine binding to its cell surface receptors with oral therapies offers the promise to bring forward biologics-like efficacy in a pill to patients. We used an NMR-based fragment screen of recombinant IL17A to uncover starting points for small molecule IL17A antagonist discovery. By examining chemical shift perturbations in 2D [ 1 H, 13 C-HSQC] spectra of isotopically labeled IL17A, we discovered fragments binding the cytokine at a previously undescribed site near the IL17A C-terminal region, albeit with weak affinity (> 250 µM). Importantly this binding location was distinct from previously known chemical matter modulating cytokine responses. Subsequently through analog screening, we identified related compounds that bound symmetrically in this novel site with two copies. From this observation we employed a linking strategy via structure-based drug design and obtained compounds with increased binding affinity (< 50 nM) and showed functional inhibition of IL17A-induced cellular signaling (IC 50 ~1 µM). We also describe a fluorescence-based probe molecule suitable to discern/screen for additional molecules binding in this C-terminal site.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-022-18760-1