title: Targeting the binding interface on a shared receptor subunit of a cytokine family enables the inhibition of multiple member cytokines with selectable target spectrum.
abstract: The common γ molecule (γc) is a shared signaling receptor subunit used by six γc-cytokines. These cytokines play crucial roles in the differentiation of the mature immune system and are involved in many human diseases. Moreover, recent studies suggest that multiple γc-cytokines are pathogenically involved in a single disease, thus making the shared γc-molecule a logical target for therapeutic intervention. However, the current therapeutic strategies seem to lack options to treat such cases, partly because of the lack of appropriate neutralizing antibodies recognizing the γc and, more importantly, because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the γc and cytokines, we successfully designed peptides that not only inhibit multiple γc-cytokines but with a selectable target spectrum. Notably, the lead peptide inhibited three γc-cytokines without affecting the other three or non-γc-cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of γc-cytokines the γc-molecule. Furthermore, we provide evidence that our peptide, when conjugated to polyethylene glycol to gain stability in vivo, efficiently blocks the action of one of the target cytokines in animal models. Collectively, our technology can be expanded to target various combinations of γc-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory, and malignant diseases.
authors.affiliation: From the Cell Biology Laboratory, Division of Basic Science, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Toshie
authors.initials: T
authors.lastname: Nata
authors.affiliation: BIONIZ Inc., Irvine, California 92618, and.
authors.forename: Asjad
authors.initials: A
authors.lastname: Basheer
authors.affiliation: From the Cell Biology Laboratory, Division of Basic Science, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Cocchi
authors.affiliation: From the Cell Biology Laboratory, Division of Basic Science, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Richard
authors.initials: R
authors.lastname: van Besien
authors.affiliation: the Section of Neuroimmunology, NINDS, National Institutes of Health, Bethesda, Maryland 20890.
authors.forename: Raya
authors.initials: R
authors.lastname: Massoud
authors.affiliation: the Section of Neuroimmunology, NINDS, National Institutes of Health, Bethesda, Maryland 20890.
authors.forename: Steven
authors.initials: S
authors.lastname: Jacobson
authors.affiliation: BIONIZ Inc., Irvine, California 92618, and.
authors.forename: Nazli
authors.initials: N
authors.lastname: Azimi
authors.affiliation: From the Cell Biology Laboratory, Division of Basic Science, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201, ytagaya@ihv.umaryland.edu.
authors.forename: Yutaka
authors.identifier: http://orcid.org/0000-0002-1342-9282
authors.initials: Y
authors.lastname: Tagaya
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*
chemical_list: D016207:Cytokines; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D010455:Peptides
keywords: cell proliferation; cytokine action; drug design; interleukin; peptide interaction