Slimming the Waste-Line in Peptide and Oligonucleotide Syntheses

Organizer: Michael Kopach, Senior Research Advisor, Eli Lilly

Peptides have gained increased interest as therapeutics over the past few decades, largely due to their advantageous properties including high specificity and affinity, as well as superior safety and tolerance. These properties make peptide drugs more desirable than small molecule drugs in select disease classes including cancer, diabetes, degenerative and infectious diseases. Currently, there are over 60 FDA approved peptide drugs on the market and over 600 either in clinical trials or pre-clinical development. Peptide-based therapeutic agents have the potential to replace many existing small molecule-based therapies in the near future. Likewise great strides have been made in oligonucleotide therapies and delivery technologies over the past five years.

Compared to the synthetic processes for small molecule drugs, the environmental impact of this technology has not garnered much attention, in part because the high potency of peptide and oligonucleotide drugs has rendered supply needs significantly lower than traditional small molecule drugs. However, market forecasts indicate potential for a significant increase in high volume peptide and oligonucleotide processes. Recent investigations have revealed that, on average, producing 1 kg of peptide or oligonucleotide products require over 5 to 15 metric tons of solvent, significantly higher than all types of synthetic small molecule. In addition, the current state of the art in peptide and oligonucleotide syntheses utilize primarily legacy technologies, with little focus on green chemistry and engineering with multiple usages of highly hazardous reagents and solvents. Contributing to the poor environmental profile for peptide and oligonucleotide products is the ubiquitous use of chromatography. Recognizing these unmet environmental needs the ACS Pharmaceutical Roundtable recently founded a team focused on improving sustainability practices in peptide and oligonucleotide syntheses. The groups initial contribution is focused on stimulating innovations in peptide syntheses (J. Org. Chem., 2019, 84 (8), pp 4615–4628). This session will explore how improved synthetic methodologies, safer coupling reagents, solvent selection, and minimization of chromatography play a vital role in improving the sustainability both peptide and oligonucleotide syntheses.

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