Modulators of gamma-C-cytokine activity
Peptide antagonists of γc-family cytokines, which is associated with important human diseases, such as leukemia, autoimmune diseases, collagen diseases, diabetes mellitus, skin diseases, degenerative neuronal diseases and graft-versus-host disease (GvHD). Thus, inhibitors of γc-cytokine activity are valuable therapeutic and cosmetic agents as well as research tools. Traditional approaches to inhibiting γc-cytokine activity involve raising neutralizing antibodies against each individual γc-cytokine family member/receptor subunit. However, success has been limited and often multiple γc-cytokine family members co-operate to cause the disease state. Combinatorial use of neutralizing antibodies raised against each factor is impractical and poses an increased risk of adverse immune reactions. The present embodiments overcome these shortcomings by utilizing peptide antagonists based on the consensus γc-subunit binding site to inhibit γc-cytokine activity. Such approach allows for flexibility in antagonist design. The disclosed peptides exhibit Simul-Block activity, inhibiting the activity of multiple γc-cytokine family members.
1. A composite peptide, or a derivative thereof, that comprises amino acid sequences of at least two interleukin (IL) protein gamma-c-box D helix regions, wherein the composite peptide comprises the amino acid sequence P-K-E-F-L-E-R-F-V-H-L-V-Q-M-F-I-H-Q-S-L-S (SEQ ID NO: 3), wherein the derivative thereof comprises a peptide sequence sharing at least 90% identity with the amino acid sequence of SEQ ID NO: 3, and wherein the composite peptide or the derivative thereof inhibits the activity of at least IL-15 and IL-21.
2. The composite peptide, or the derivative thereof, of claim 1 , further comprising a signal peptide.
3. The composite peptide, or the derivative thereof, of claim 1 , wherein the composite peptide or the derivative thereof is further conjugated to one or more additional moieties at the N-terminus, C-terminus, or a side residue of the composite peptide.
4. The composite peptide, or the derivative thereof, of claim 3 , wherein the one or more additional moieties are selected from the group consisting of bovine serum albumin (BSA), albumin, Keyhole Limpet Hemocyanin (KLH), Fc region of IgG, a biological protein that acts as a scaffold, an antibody against a cell-specific antigen, a receptor, a ligand, a metal ion, and Poly Ethylene Glycol (PEG).
5. A pharmaceutical composition comprising:
a peptide conjugate, or a derivative thereof, wherein the peptide conjugate comprises the amino acid sequence P-K-E-F-L-E-R-F-V-H-L-V-Q-M-F-I-H-Q-S-L-S (SEQ ID NO: 3),
wherein the derivative thereof comprises a peptide sequence sharing at least 90% identity with the amino acid sequence of SEQ ID NO: 3,
and wherein the peptide conjugate or the derivative thereof inhibits the activity of at least IL-15and IL-21.
6. The pharmaceutical composition of claim 5 , wherein the derivative thereof comprises a peptide sequence sharing at least 95% identity with the amino acid sequence of SEQ ID NO: 3.
7. The pharmaceutical composition of claim 5 , wherein the peptide conjugate or the derivative thereof further comprises a signal peptide.
8. The pharmaceutical composition of claim 5 , wherein the peptide conjugate or the derivative thereof further comprises an additional conjugate at the N-termini, C-termini or a side residue thereof.
9. The pharmaceutical composition of claim 5 , further comprising a protein that stabilizes the structure of the peptide conjugate or the derivative thereof and improves its biological activity.
10. The pharmaceutical composition of claim 9 , wherein the protein is selected from the group consisting of bovine serum albumin (BSA), albumin, Fc region of immunoglobulin G (IgG), biological proteins that function as scaffold, Poly Ethylene Glycol (PEG), and derivatives thereof.