Novel TAPS-ASAL method enables sustainable, low-epimerization synthesis of long therapeutic peptides like tirzepatide

The growing demand for therapeutic peptides necessitates sustainable and cost-effective alternatives to traditional solid-phase peptide synthesis (SPPS). While tag-assisted peptide synthesis (TAPS) offers promise, its utility is limited for longer peptides exceeding 20 residues. Fragment condensation, an alternative for larger targets, often leads to unacceptable levels of epimerization without extensive optimization. This gap highlights the need for a robust, environmentally friendly method to synthesize complex, pharmaceutically relevant peptides without compromising purity or efficiency.

Researchers developed an efficient platform for synthesizing pharmaceutically relevant peptides by integrating aryl selenoester aminolysis ligation (ASAL) into the existing Tag-Assisted Peptide Synthesis (TAPS) workflow. This novel ligation method directly utilizes peptide aryl selenoesters generated via TAPS. The team then applied this combined TAPS-ASAL methodology to achieve the convergent synthesis of several complex therapeutic peptides. These included the osteoporosis drug teriparatide (34 residues), the sulfated tsetse fly-derived thrombin-inhibiting anticoagulant TTI (32 residues), and tirzepatide (39 residues), which is used for type 2 diabetes and weight management.

The novel TAPS-ASAL ligation method successfully circumvented the inherent peptide length limitations previously associated with Tag-Assisted Peptide Synthesis (TAPS), making it suitable for assembling peptides exceeding 20 residues. A key finding was that this approach consistently led to minimal epimerization, a significant advantage over traditional fragment condensation methods which often require extensive optimization to prevent this issue. Furthermore, the integrated TAPS-ASAL workflow demonstrated a significant reduction in both reagent and solvent use, making it highly attractive from an environmental sustainability perspective. The platform's robustness was validated through the successful convergent synthesis of several complex therapeutic peptides. > This included the efficient production of teriparatide (a 34-residue peptide), TTI (a 32-residue peptide), and tirzepatide (a 39-residue peptide), showcasing its capability for diverse and challenging targets.