Chimeric neuregulins and method of making and use thereof

摘要

Composition containing a chimeric neuregulin polypeptides and method of making such polypeptides are disclosed. The chimeric neuregulin comprises a first moiety of at least 10 amino acids, wherein the first moiety is derived from a first polypeptide; and a second moiety of at least 5 amino acids, wherein the second moiety is derived from a second polypeptide; wherein the first polypeptide is a neuregulin and the chimeric neuregulin exhibits an enhanced binding affinity to integrin, Erb 3, or Erb 4 comparing to that of the first neuregulin.

主权项

1. A method for ameliorating neuronal damage in a subject, comprising: administering to said subject an effective amount of a pharmaceutical composition comprising: a chimeric neuregulin polypeptide having an integrin domain that binds to an integrin and an ErbB3/B4 binding domain that binds to ErbB3 and/or ErbB4, said chimeric neuregulin polypeptide comprising: a neuregulin backbone derived from a native neuregulin polypeptide, said neuregulin backbone comprising an ErbB3/B4 binding domain; and a donor fragment comprising a polypeptide derived from another neuregulin that is different from said native neuregulin, said donor fragment comprising an integrin binding domain, wherein said chimeric neuregulin comprises a neuregulin consensus motif comprising six cysteine residues spread in a region spanning an integrin binding domain and an ErbB3/ErbB4 binding domain and wherein said integrin binding domain comprises two positively charged amino acids at the amino-end of the first cysteine in the neuregulin consensus sequence, wherein the chimeric neuregulin polypeptide comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 23, 24, 27 and 28, and a pharmaceutically acceptable carrier.