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

  • Sci Rep. 2016 Aug 16;6:30859. doi: 10.1038/srep30859.
Shenping Liu  1 ,  Leslie A Dakin  2 ,  Li Xing  2 ,  Jane M Withka  1 ,  Parag V Sahasrabudhe  1 ,  Wei Li  3 ,  Mary Ellen Banker  4 ,  Paul Balbo  3 ,  Suman Shanker  1 ,  Boris A Chrunyk  1 ,  Zuojun Guo  2 ,  Jinshan M Chen  1 ,  Jennifer A Young  1 ,  Guoyun Bai  1 ,  Jeremy T Starr  1 ,  Stephen W Wright  1 ,  Joerg Bussenius  5 ,  Sheng Tan  5 ,  Ariamala Gopalsamy  2 ,  Bruce A Lefker  2 ,  Fabien Vincent  4 ,  Lyn H Jones  2 ,  Hua Xu  2 ,  Lise R Hoth  1 ,  Kieran F Geoghegan  1 ,  Xiayang Qiu  1 ,  Mark E Bunnage  2 ,  Atli Thorarensen  2
Affiliations
  • 1. Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
  • 2. Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
  • 3. Inflammation and Immunoscience Research Unit, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
  • 4. Primary Pharmacology Group, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
  • 5. WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
PMID: 27527709 DOI: 10.1038/srep30859
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.

Products