Peptide Couplings by Reactive Extrusion: Solid-Tolerant and Free from Carcinogenic, Mutagenic and Reprotoxic Chemicals

Abstract

Industrial peptide synthesis is generally carried out in batches and suffers both from the production of tremendous amounts of toxic waste and the difficulty to handle solids. In this study, peptide couplings were performed at the multigram scale by using reactive extrusion in a CMRfree (CMR = Carcinogenic, Mutagenic or Reprotoxic), solidtolerant, fast, efficient and epimerization-free manner, opening the way for intensified and continuous industrial production of peptides.

Mechanoenzymatic Transformations in the Absence of Bulk Water: A More Natural Way of Using Enzymes

“…Mechanochemical reactions, which proceed either in the absence or with very small quantities of a liquid additive, present a novel approach to control the reactivity of proteases. Mechanochemical nonenzymatic solid‐state approaches for dipeptide and oligopeptide synthesis have been shown to surpass solution synthesis and even SPPS in terms of shorter reaction times, improved product purity and reduced environmental impact …”

“…[107] High volumes of organic solvents and/or continuous removal of the water produced during synthesis are however often necessary to avoid the competing hydrolytic activity of proteases,t hus introducing enzyme stability and substrate solubility issues. [108] Mechanochemical reactions, which proceed either in the absence or with very small quantities of al iquid additive, present an ovel approacht oc ontrol the reactivity of proteases.M echanochemicaln onenzymatic solid-state approaches ford ipeptide and oligopeptide synthesis [109][110][111][112][113] have been shown to surpasss olution synthesis and even SPPS in terms of shorterr eaction times, improved product purity and reduced environmental impact. [114,115]…”

Peptide Couplings By Reactive Extrusion: Efficient, ContinuousAnd Green

“…In conclusion, dipeptides and tri-peptides can be produced in high yields, high stereoisomeric excesses and very short reaction times by using reactive extrusion. [11] The capacity to implement synthesis under continuous conditions is clearly setting the path to intensified industrial peptide production. On the contrary to synthesis in solvent-based continuous flow and i n S PPS, the presence of solids could be very easily handled by the mechanical forces occurring in the extruder.…”

Synthesis of acylglycerol derivatives by mechanochemistry

“…Not surprisingly, the natural ability of peptides to endure mechanical stress in nature has allured scientists to evaluate the mechanical stability of proteins by using single-molecule nanomechanical techniques (e.g., magnetic and optical tweezers or atomic force microscopy) [3–4]. Additionally, the resilience of the peptide bond to mechanical loads has led to mechanoenzymatic transformations [5–7], and to synthesize amino acid derivatives [8–10] and peptides [11–13] by ball milling and extrusion techniques. Similarly, mechanochemical derivatizations of sugars and sugar derivatives such as cyclodextrins (CDs) have proven compatible with the use of ball mills.…”