Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists

Liu, Shenping<sup>*</sup>; Dakin, Leslie A.<sup>*</sup>; Xing, Li; Withka, Jane M.; Sahasrabudhe, Parag V.; Li, Wei; Banker, Mary Ellen; Balbo, Paul; Shanker, Suman; Chrunyk, Boris A.; Guo, Zuojun; Chen, Jinshan M.; Young, Jennifer A.; Bai, Guoyun; Starr, Jeremy T.; Wright, Stephen W.; Bussenius, Joerg; Tan, Sheng; Gopalsamy, Ariamala; Lefker, Bruce A.; Vincent, Fabien; Jones, Lyn H.; Xu, Hua; Hoth, Lise R.; Geoghegan, Kieran F.; Qiu, Xiayang; Bunnage, Mark E.; Thorarensen, Atli

doi:10.1038/srep30859

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Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists

作者：Liu, Shenping^*; Dakin, Leslie A.^*; Xing, Li; Withka, Jane M.; Sahasrabudhe, Parag V.; Li, Wei; Banker, Mary Ellen; Balbo, Paul; Shanker, Suman; Chrunyk, Boris A.; Guo, Zuojun; Chen, Jinshan M.; Young, Jennifer A.; Bai, Guoyun; Starr, Jeremy T.; Wright, Stephen W.; Bussenius, Joerg; Tan, Sheng; Gopalsamy, Ariamala; Lefker, Bruce A.; Vincent, Fabien; Jones, Lyn H.; Xu, Hua; Hoth, Lise R.; Geoghegan, Kieran F.; Qiu, Xiayang; Bunnage, Mark E.; Thorarensen, Atli

来源：Scientific Reports, 2016, 6(1): 30859.

DOI：10.1038/srep30859

摘要

Interleukin-17A (IL-17A) is a principal driver of multiple inflammatory and immune disorders. Antibodies that neutralize IL-17A or its receptor (IL-17RA) deliver efficacy in autoimmune diseases, but no small-molecule IL-17A antagonists have yet progressed into clinical trials. Investigation of a series of linear peptide ligands to IL-17A and characterization of their binding site has enabled the design of novel macrocyclic ligands that are themselves potent IL-17A antagonists.