Site-specific modification of proteins through chemical modification enabling protein conjugates, protein dimer formation, and stapled peptides

摘要

The present invention generally provides methods for the site-specific modification of peptides, polypeptides, and proteins, e.g., granulocyte macrophage colony-stimulating factor, human superoxide dismutase, annexin, leptin, antibodies and the like, cytokines and chemokines, at their N-termini and at sites at which unnatural aminoacids have been introduced along the protein framework. The modifications described herein can be used for the synthesis and application of the adducts in radio-labeling, molecular imaging and protein therapeutic applications, and the treatment of disorders such as rheumatoid arthritis, lupus erythematosus, psoriasis, multiple sclerosis, type-1 diabetes, Crohn's disease, and systemic sclerosis, Alzheimer disease, cancer, liver disease (e.g., alcoholic liver disease), and cachexia.

主权项

1. A method of site specifically producing a covalently linked multimeric protein comprising:
(i) providing one or more proteins, wherein said one or more proteins is:
(a) a four helix bundle protein or comprises a zipper binding motif;(b) in the form of a multimer, wherein said one or more proteins are non-covalently bound to each other within said multimer; and(c) a polypeptide comprising a glycine or alanine residue at the N-terminus; and (ii) combining a bifunctional linker and said one or more proteins, wherein said bifunctional linker forms a covalent bond to said glycine or alanine residue in each protein to produce a covalently linked multimer, and wherein said bifunctional linker comprises two or more carbonyl groups.