Targeting the binding interface on a shared receptor subunit of a cytokine family enables the inhibition of multiple member cytokines with selectable target spectrum

J Biol Chem. 2015 Sep 11;290(37):22338-51. doi: 10.1074/jbc.M115.661074. Epub 2015 Jul 16.


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.

Keywords: cell proliferation; cytokine action; drug design; interleukin; peptide interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Cytokines / antagonists & inhibitors*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Female
  • Humans
  • Interleukin Receptor Common gamma Subunit / antagonists & inhibitors*
  • Interleukin Receptor Common gamma Subunit / genetics
  • Interleukin Receptor Common gamma Subunit / metabolism
  • Male
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / pharmacology*


  • Cytokines
  • IL2RG protein, human
  • Interleukin Receptor Common gamma Subunit
  • Peptides