Ligands modified by circular permutation as agonists and antagonists

摘要

The present invention provides fusion polypeptides comprising polypeptide ligands that are modified by circular permutation and fused to at least one polypeptide fusion partner wherein such fusion polypeptides have new, improved or enhanced biological functions or activities. Such improvements include, but are not limited to, increased binding affinity, increased activity, increased agonist activity (super agonist), antagonist activity, increased accessibility, increased flexibility of the active site, increased stability, broader and/or changed substrate specificity, and combinations thereof.

主权项

1. A fusion polypeptide comprising, a first polypeptide fusion partner linked to a modified ligand corresponding to all or a portion of a native ligand of a target receptor, wherein the modified ligand has been circularly permuted to create a new N-terminus and a new C-terminus as compared to the native ligand, and wherein the new N-terminus or the new C-terminus of the modified ligand is linked to a first polypeptide fusion partner to form a fusion polypeptide wherein the new C-terminus and the new N-terminus of the modified ligand do not disrupt any binding domain of the modified ligand for the target receptor and wherein the modified ligand optionally has increased affinity for the target receptor as compared to the native ligand for the receptor, wherein the target receptor functions by stepwise formation of a multimeric activation complex to trigger signal transduction of a signaling cellular pathway and wherein when the fusion polypeptide binds the receptor it either enhances the stepwise formation of the multimeric activation complex thereby super agonizing signal transduction by the target receptor or it sterically hinders the stepwise formation of the multimeric complex thereby antagonizing signal transduction by the target receptor wherein the fusion polypeptide comprises amino acids 1-303 of SEQ ID NO: 26.