title: Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide.
abstract: IL-17A is a pro-inflammatory cytokine that has been implicated in autoimmune and inflammatory diseases. Monoclonal antibodies inhibiting IL-17A signaling have demonstrated remarkable efficacy, but an oral therapy is still lacking. A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions. HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. Tested in primary human cells, HAP blocked the production of multiple inflammatory cytokines. Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. The N-terminal portions of HAP form a β-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. This mode of inhibition suggests opportunities for developing peptide antagonists against this challenging target.
authors.affiliation: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340 USA.
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Desharnais
authors.affiliation: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340 USA.
authors.forename: Parag V
authors.initials: PV
authors.lastname: Sahasrabudhe
authors.affiliation: Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.affiliation: Worldwide Research and Development, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Oates
authors.affiliation: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340 USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Shanker
authors.affiliation: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340 USA.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Banker
authors.affiliation: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340 USA.
authors.forename: Boris A
authors.initials: BA
authors.lastname: Chrunyk
authors.affiliation: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340 USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Song
authors.affiliation: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340 USA.
authors.forename: Xidong
authors.initials: X
authors.lastname: Feng
authors.affiliation: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340 USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Griffor
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, San Diego, CA 92037, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Jimenez
authors.affiliation: Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: David
authors.initials: D
authors.lastname: Tumelty
authors.affiliation: Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Bhat
authors.affiliation: Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: Curt W
authors.initials: CW
authors.lastname: Bradshaw
authors.affiliation: Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Woodnutt
authors.affiliation: Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Lappe
authors.affiliation: Worldwide Research and Development, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Atli
authors.initials: A
authors.lastname: Thorarensen
authors.affiliation: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340 USA.
authors.forename: Xiayang
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340 USA.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Withka
authors.affiliation: Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.|Worldwide Research and Development, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Lauren D
authors.initials: LD
authors.lastname: Wood
mesh_terms: D019943:Amino Acid Substitution; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008403:Mass Screening; D008958:Models, Molecular; D016296:Mutagenesis; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D053722:Receptors, Interleukin-17 / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C508717:IL17A protein, human; C109985:IL17RA protein, human; D020381:Interleukin-17; D019151:Peptide Library; D010455:Peptides; D053722:Receptors, Interleukin-17