| Autor: |
Eric R. Goedken, Maria A. Argiriadi, Justin D. Dietrich, Andrew M. Petros, Navasona Krishnan, Sanjay C. Panchal, Wei Qiu, Haihong Wu, Haizhong Zhu, Ashley M. Adams, Pierre M. Bodelle, Lucas Goguen, Paul L. Richardson, Peter F. Slivka, Myron Srikumaran, Anup K. Upadhyay, Bainan Wu, Russell A. Judge, Anil Vasudevan, Sujatha M. Gopalakrishnan, Philip B. Cox, Vincent S. Stoll, Chaohong Sun |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Scientific Reports, Vol 12, Iss 1, Pp 1-12 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2045-2322 |
| DOI: |
10.1038/s41598-022-18760-1 |
| Popis: |
Abstract 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 [1H, 13C-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 ( |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
|
Nepřihlášeným uživatelům se plný text nezobrazuje |
K zobrazení výsledku je třeba se přihlásit.
|
