Antagonists of ligands and uses thereof

A method of designing a hetero-multivalent linker useful in modulating responsiveness of a cell to a member of the TGF-β superfamily, said method comprising:

• a) identifying a member of the TGF-β superfamily of interest;
• b) obtaining at least two different polypeptide binding domains having affinity for different sites on the same member or for different members of the TGF-β superfamily;
• c) obtaining an unstructured polypeptide linker of at least a number of amino acids equal to (X/2.5), wherein the number of amino acids in each linker is determined independently and is greater than or equal to X/2.5, where X equals the shortest linear distance between:
• (i) the C-terminus of an isolated form of the binding domain that is located at the N-terminus of the linker and that is specifically bound to its ligand;
• and,
• (ii) the N-terminus of an isolated form of the binding domain that is located at the C-terminus of the linker and that is specifically bound to its ligand;
• and
• d) modeling the linker having one of the binding domains covalently attached at each end, and carrying out molecular mechanics and/or dynamics simulations to substantially minimize the interaction energy and reduce steric and electrostatic incompatibility between the linker and the member of the TGF-β superfamily.