Towards Sustainable Synthesis of Peptide Therapeutics via Tag-Assisted Peptide Synthesis and Aryl Selenoester Aminolysis Ligation

There has been a recent renaissance in the use of peptides as therapeutic agents across a range of indications, sparking significant demand for the development of sustainable and cost-effective alternatives to solid-phase peptide synthesis (SPPS) for the production of these molecules, particularly in the pharmaceutical industry. While tag-assisted peptide synthesis (TAPS) has offered promise, this methodology cannot be routinely used to assemble longer peptide targets (>20 residues), limiting its utility for most peptide therapeutics. Fragment condensation of side-chain-protected peptides using coupling reagents is typically used to prepare larger targets, but this approach usually leads to unacceptable levels of epimerization without significant optimization. Herein, we report an efficient platform for the synthesis of pharmaceutically relevant peptides through direct aminolysis of peptide aryl selenoesters generated via TAPS. Notably, this novel ligation method circumvents the limitations of peptide length associated with TAPS, leads to minimal epimerization, and significantly reduces reagent and solvent use, making it attractive from an environmental standpoint. By integrating the aryl selenoester aminolysis ligation (ASAL) into the TAPS workflow, the convergent synthesis of several therapeutic peptides of increasing complexity was successfully accomplished, including osteoporosis drug teriparatide (34 residues), sulfated tsetse fly-derived thrombin-inhibiting anticoagulant TTI (32 residues), and tirzepatide (39 residues), used for the treatment of type 2 diabetes and weight management. When used in concert with TAPS, the ASAL reaction developed here can serve as a robust method for the ligation-based assembly of tagged peptides, creating a scalable route to access peptide-based therapeutics across academia and industry with a low environmental impact.