Tirzepatide, a 39-amino acid synthetic peptide, is a once-weekly novel dual GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like-peptide-1) receptor agonist. Tirzepatide is in phase 3 clinical development at Eli Lilly and Company for blood glucose management in adults with type 2 diabetes, chronic weight management, and for obesity related heart failure with preserved ejection fraction. In addition, Tirzepatide is being studied as a potential treatment for non-alcoholic steatohepatitis (NASH). The Tirzepatide sequence consists of a 39 amino acid peptide backbone containing the non-coded amino acid aminoisobutyric acid (Aib) in two positions, a C-terminus amide, as well as a C20 fatty acid moiety covalently attached at lysine 20.
Many challenges exist in developing reliable processes to manufacture high volume complex synthetic peptides due to inherent limitations of Solid Phase Peptide Synthesis (SPPS) and Liquid Phase Peptide Synthesis (SPPS). These challenges were overcome by developing a four fragment Hybrid SPPS/LPPS process which takes advantage of the best features of both synthetic strategies. Though the convergent hybrid synthesis strategy is a very appealing substitute to the linear SPPS, there is a need in the peptide industry for more efficient and greener hybrid syntheses. Native chemical ligation (NCL) is a powerful methodology to synthesize large polypeptides and proteins utilized in academia, but to date does not have any known commercial implementations. Herein, we have developed an NCL synthesis for Tirzepatide where two unprotected peptide fragments are coupled in aqueous media without any epimerization. The tandem chemoselective fragment ligation / desulfurization approach is potentially the greenest of all hybrid approaches to produce a synthetic peptide.

Subject area:
Biologics

Objectives (If applicable):
N/A

Target Audience (If applicable):
Analytical chemists
QA/QC analysts
R&D scientists, managers
Team members in CMC development projects
Manufacturing scientists, managers
Regulatory affairs specialists
Contract research organizations
Contract manufacturing organizations