Modified GLP-1/GIP Polypeptide for Stable NASH Therapy

The patent modifies the polypeptide sequence parameters by introducing specific amino acid substitutions (e.g., lysine to arginine at positions 17 and 20), adding amino acid residues, or modifying the C-terminal end (including amidation of serine at position 39). These parameter changes create modified polypeptides with enhanced pharmacokinetic properties and plasma stability while maintaining GLP-1R/GIPR agonistic activity, thereby improving treatment reliability for NASH.

The patent applies local quality modification by making specific changes at particular positions in the polypeptide sequence rather than random modifications. Key modifications include: substituting amino acids at specific positions (e.g., lysine to arginine at positions 17 and 20), adding amino acid residues at defined locations, and modifying the C-terminal end (including amidation of serine at position 39). These localized modifications enhance plasma stability and pharmacokinetic properties while maintaining manageable molecular complexity.

The patent segments the modification process into distinct categories: amino acid substitutions at specific positions, addition of amino acid residues, and C-terminal modifications (including amidation). This segmentation allows for systematic exploration of modification combinations, where each category can be independently optimized and synthesized. The segmented approach maintains therapeutic efficacy while facilitating manageable synthesis and manufacturing processes.