Survodutide

Survodutide (BI 456906) is a synthetic peptide dual agonist of the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R), a pharmacology modelled on the gut peptide oxyntomodulin, which activates both receptors. It is acylated with a C18 fatty acid that serves as its half-life-extending modification. The molecule has the formula C192H289N47O61 and a molar mass of about 4,232 g/mol. It was selected from a series of 19 dual agonists profiled for balanced activity at the two receptors.

Survodutide in the research literature

Receptor potencies were profiled with cyclic AMP assays in recombinant cell lines, in the mouse pancreatic beta-cell line MIN6 for GLP-1R and in primary rat hepatocytes for GCGR. In mice, GCGR engagement was tracked with liver nicotinamide N-methyltransferase mRNA, plasma FGF21 and circulating amino acids, and dual receptor activity was supported using GLP-1R knockout mice, transgenic reporter mice and an ex vivo bioactivity assay.

In rodent models of energy balance, fluorophore-labelled survodutide was observed to access the circumventricular organs of the mouse brain and adjacent hypothalamic and hindbrain nuclei without evidence of uniformly crossing the blood-brain barrier. c-Fos mapping showed activation of multiple nuclei, and comparison with a long-acting GCGR agonist indicated that the central neuronal activation pattern is GLP-1R dependent.