title: Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists.
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.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Dakin
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Withka
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Parag V
authors.initials: PV
authors.lastname: Sahasrabudhe
authors.affiliation: Inflammation and Immunoscience Research Unit, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Primary Pharmacology Group, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Banker
authors.affiliation: Inflammation and Immunoscience Research Unit, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Balbo
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Shanker
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Boris A
authors.initials: BA
authors.lastname: Chrunyk
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Zuojun
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Jinshan M
authors.initials: JM
authors.lastname: Chen
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Young
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Guoyun
authors.initials: G
authors.lastname: Bai
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Jeremy T
authors.initials: JT
authors.lastname: Starr
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wright
authors.affiliation: WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Joerg
authors.initials: J
authors.lastname: Bussenius
authors.affiliation: WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Tan
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Ariamala
authors.initials: A
authors.lastname: Gopalsamy
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Lefker
authors.affiliation: Primary Pharmacology Group, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Vincent
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Lyn H
authors.initials: LH
authors.lastname: Jones
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Lise R
authors.initials: LR
authors.lastname: Hoth
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Kieran F
authors.initials: KF
authors.lastname: Geoghegan
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Xiayang
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bunnage
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Atli
authors.initials: A
authors.lastname: Thorarensen
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C508717:IL17A protein, human; D020381:Interleukin-17; D047028:Macrocyclic Compounds; D010456:Peptides, Cyclic; D054852:Small Molecule Libraries