Greening the synthesis of peptide therapeutics: an industrial perspective

Abstract

This review highlights the efforts made to date to promote greener peptide synthesis, from an industrial perspective.

Harnessing polarity and viscosity to identify green binary solvent mixtures as viable alternatives to DMF in solid-phase peptide synthesis

“…If these qualities are met, technical challenges in the pilot plant environment can be minimised and product output and manufacturing time kept at an acceptable level. 24,25,42 • Solvent melting point ≤ 10°C…”

“…In the search for a DMF substitute in large-scale SPPS, we have therefore decided to focus on environmental and safety aspects based on the ECHA-REACH status, and herein we define green solvents from this perspective. 21 Significant work has been done by teams in both academia and industry over the last decade in making peptide synthesis greener, [22][23][24][25] with recent focus on solvent substitution, reduction and recycling in SPPS. More benign solvents investigated for use in various stages of the SPPS process include acetonitrile (MeCN), 26,27 2-methyl tetrahydrofuran (2-Me-THF), [28][29][30][31] ethyl acetate (EtOAc), 27,29,31 anisole, 27 dimethyl carbonate (DMC), 27,31 N-butylpyrrolidone (NBP), 11,31,32 γ-valerolactone (GVL), 31,[33][34][35][36][37] cyclopentyl methyl ether (CPME), 30,31 4-methyl tetrahydropyran (MTHP), 31 and N-formylmorpholine (NFM).…”

“…Moreover, recycling specific solvents such as DMSO by distillation is associated with safety concerns, 41 and hence for a green solvent or solvent mixture to be impactful across industry and academia there are a number of technical and regulatory requirements that need to be fulfilled, which has been thoroughly discussed in recent reviews. 11,24,25,42 Furthermore, it is becoming increasingly clear that intrinsic solvent properties such as polarity, are of utmost importance for SPPS process performance. 11,38,39 In this project, we set out to identify environmentally benign solvents or solvent mixtures amenable to large-scale SPPS of therapeutic-grade peptides.…”

Replacing DMF in solid-phase peptide synthesis: varying the composition of green binary solvent mixtures as a tool to mitigate common side-reactions

“…8 In recent years, this has triggered considerable research into identifying greener and less toxic alternatives to especially DMF in SPPS. [9][10][11][12] We have found that binary mixtures of green solvents (e.g. dimethyl sulfoxide (DMSO)/ethyl acetate (EtOAc), DMSO/1,3-dioxolane (DOL), and DMSO/2-methyl tetrahydrofuran (2-Me-THF) that display similar polarity and viscosity profiles to DMF are viable, less toxic solvent alternatives to DMF in SPPS.…”

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

“…However, this promising treatment is affected by administration issues owing to the difficulties of atrial natriuretic peptides in penetrating the cornea to lower IOP. To overcome this drawback, TAK639 was designed as a cornea-permeable CNP derivative, exhibiting increased production and cellular concentrations of cyclic guanosine monophosphate (cGMP), able to lower IOP ( Martin V. et al, 2020 ).…”