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 ? molecule (?c) is a shared signaling receptor subunit used by six ?c-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 ?c-cytokines are pathogenically involved in a single disease, thus making the shared ?c-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 ?c and, more importantly, because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the ?c and cytokines, we successfully designed peptides that not only inhibit multiple ?c-cytokines but with a selectable target spectrum. Notably, the lead peptide inhibited three ?c-cytokines without affecting the other three or non-?c-cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of ?c-cytokines the ?c-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 ?c-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory, and malignant diseases.

SUBMITTER: Nata T 

PROVIDER: S-EPMC4566211 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature