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

• Published in: Scientific reports Vol. 6; no. 1; p. 30859
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-08-2016; Nature Publishing Group
• Subjects: 631/154/309/2419; 631/154/309/2420; 631/250/256/2516; Algorithms; Antibodies; Autoimmune diseases; Binding Sites; Cells, Cultured; Clinical trials; Drug Design; Humanities and Social Sciences; Humans; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - chemistry; Keratinocytes - cytology; Keratinocytes - drug effects; Keratinocytes - metabolism; Ligands; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Molecular Dynamics Simulation; multidisciplinary; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Protein Binding; Science; Science (multidisciplinary); Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep30859

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.