Methods of developing selective peptide antagonists

A method of producing a chimeric composite peptide(s) comprising a first inhibitor polypeptide of a first ligand-receptor complex and a second ligand-receptor complex, the method comprising:

• using a computer to obtain amino acid sequences of a first ligand and a second ligand from an amino acid sequence database;
• generating 3D renditions of receptor binding interactions by one or both of the following methods:
• performing computer-assisted docking simulations for the first ligand-receptor complex and the second ligand-receptor complex based on the obtained amino acid sequences, and
• analyzing the crystal structures of the first ligand-receptor complex and the second ligand-receptor complex;
• identifying from the 3D renditions specific amino acid sequence fragments and one or more structurally conserved regions common to the first ligand and the second ligand, wherein the one or more common structurally conserved regions of the first ligand interact with a receptor of the first ligand, and the one or more common structurally conserved regions of the second ligand interact with a receptor of the second ligand;
• designing candidate composite peptide(s) that contain both the specific amino acid sequence fragments and the one or more common structurally conserved regions responsible for the binding of the first ligand to the first receptor and the second ligand to the second receptor;
• screening the candidate composite peptide(s) for thermodynamic stability and proper binding;
• synthesizing by solid-phase peptide synthesis, biological synthesis, or both the candidate composite peptide(s) that exhibit both thermodynamic stability and proper binding;
• testing the synthesized candidate composite peptide(s) for binding and biological activity to identify the chimeric composite peptide(s);
• repeating one or more of the above steps if needed, and
• producing the chimeric composite peptide(s).