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

大环IL-17A拮抗剂的结合位点阐明和结构导向设计

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

Abstract

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.

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