Towards Sustainable Synthesis of Peptide Therapeutics via Tag-Assisted Peptide Synthesis and Aryl Selenoester Aminolysis Ligation.
This study presents a novel chemical synthesis methodology called Aryl Selenoester Aminolysis Ligation (ASAL), designed to overcome key limitations of existing peptide manufacturing approaches. Traditional solid-phase peptide synthesis (SPPS) is costly and resource-intensive, while tag-assisted peptide synthesis (TAPS) is generally restricted to peptides of 20 residues or fewer. Fragment condensation methods for longer peptides often produce problematic epimerization (structural errors). The researchers integrated ASAL into a TAPS workflow to enable convergent, fragment-based assembly of longer therapeutic peptides in solution. They demonstrated the platform by successfully synthesizing three clinically relevant peptides of increasing complexity: teriparatide (34 residues, used in osteoporosis treatment), a sulfated thrombin-inhibiting anticoagulant TTI (32 residues), and tirzepatide (39 residues, used for type 2 diabetes and weight management). The method reportedly minimized epimerization, reduced reagent and solvent consumption, and showed promise for scalability. Limitations include the study being purely a chemistry/methods paper with no biological testing in cells, animals, or humans — all findings are based on synthetic yield, purity, and chemical characterization metrics alone.
Why this grade: This is a synthetic chemistry methods paper with no biological assays, animal studies, or human data; all outcomes are chemical characterization metrics (yield, purity, epimerization rates).
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.
Educational summary of published research — not medical advice. Full text is shown only where licensing permits.