Albumin bound macromolecule tri-agonist activating GLP-1/GIP/glucagon receptors

A Class B G protein-coupled receptor (GPCR) agonist fusion protein, comprising:

• a conformationally modified albumin comprising a Cys34 amino acid, wherein the conformationally modified albumin is an at least partially defatted albumin;
• a GPCR agonist peptide comprising a Lys amino acid;
• and
• a linker covalently coupling the conformationally modified albumin to the GPCR agonist peptide, wherein the linker comprises a planar Michael acceptor group comprising a maleimide group or a bromo maleimide group;
• (a) wherein the linker is covalently bound to the GPCR agonist peptide via an amide bond formed by an epsilon amino group of the Lys amino acid;
• (b) wherein the linker is covalently bound to the albumin via a covalent bond between a chiral carbon atom of a coupling group in the linker and a sulfur atom in the Cys34 amino acid;
• and
• (d) wherein the chiral carbon atom has a stereopreferred or stereoselective (R) configuration and is retro-Michael resistant.

A pharmaceutical composition, comprising:

• a pharmaceutically acceptable liquid carrier in combination with a retro-Michael resistant Class B G protein-coupled receptor (GPCR) agonist fusion protein in which a GPCR agonist peptide is covalently coupled to a conformationally modified albumin via a linker;
• wherein the conformationally modified albumin is an at least partially defatted albumin,
• wherein the pharmaceutically acceptable liquid carrier is comprised of less than 1% of unbound GPCR agonist peptide;
• and
• wherein the linker comprises a chiral carbon having an (R) configuration.