An Evaluation of the Occupational Health Hazards of Peptide Couplers

Abstract

Peptide couplers (also known as amide bond-forming reagents or coupling reagents) are broadly used in organic chemical syntheses, especially in the pharmaceutical industry. Yet, occupational health hazards associated with this chemical class are largely unexplored, which is disconcerting given the intrinsic reactivity of these compounds. Several case studies involving occupational exposures reported adverse respiratory and dermal health effects, providing initial evidence of chemical sensitization. To address the paucity of toxicological data, a pharmaceutical cross-industry task force was formed to evaluate and assess the potential of these compounds to cause eye and dermal irritation as well as corrosivity and dermal sensitization. The goal of our work was to inform health and safety professionals as well as pharmaceutical and organic chemists of the occupational health hazards associated with this chemical class. To that end, 25 of the most commonly used peptide couplers and five hydrolysis products were selected for in vivo, in vitro , and in silico testing. Our findings confirmed that dermal sensitization is a concern for this chemical class with 21/25 peptide couplers testing positive for dermal sensitization and 15 of these being strong/extreme sensitizers. We also found that dermal corrosion and irritation (8/25) as well as eye irritation (9/25) were health hazards associated with peptide couplers and their hydrolysis products (4/5 were dermal irritants or corrosive and 4/5 were eye irritants). Resulting outcomes were synthesized to inform decision making in peptide coupler selection and enable data-driven hazard communication to workers. The latter includes harmonized hazard classifications, appropriate handling recommendations, and accurate safety data sheets, which support the industrial hygiene hierarchy of control strategies and risk assessment. Our study demonstrates the merits of an integrated, in vivo - in silico analysis, applied here to the skin sensitization endpoint using the Computer-Aided Discovery and REdesign (CADRE) and Derek Nexus programs. We show that experimental data can improve predictive models by filling existing data gaps while, concurrently, providing computational insights into key initiating events and elucidating the chemical structural features contributing to adverse health effects. This interactive, interdisciplinary approach is consistent with Green Chemistry principles that seek to improve the selection and design of less hazardous reagents in industrial processes and applications.

Facile Amide Bond Formation with TCFH–NMI in an Organic Laboratory Course

“…This experiment generates medicinally relevant amide products by coupling biorenewable 2-furoic acid with either of two amines using a modern, industrially inspired reagent combination of TCFH–NMI at room temperature. In comparison to other JCE methods to prepare amides, this experiment proceeds smoothly at room temperature, allows rapid product isolation by filtration, uses minimal (and relatively green) solvents, and avoids sensitizing reagents . Neither an inert atmosphere nor anhydrous solvents are required.…”

“…N -Boc-piperazine and 1-(2-pyrimidyl)­piperazine can cause skin and eye irritation. Tetramethylchloroformadinium hexafluorophosphate (TCFH) can cause skin, eye, and respiratory irritation . Acetonitrile is flammable and an eye irritant.…”

“…In addition, these conditions benefit from simple product isolation due to the water solubility of the reaction byproducts . Notably, TCFH is not a skin sensitizer, in contrast to many commonly used, modern amide bond-forming reagents such as 1-ethyl-3-(3′-dimethylaminopropyl)­carbodiimide (EDAC) or 1-[bis­(dimethylamino)­methylene]-1 H -1,2,3-triazolo­[4,5- b ]­pyridinium 3-oxide hexafluorophosphate (HATU) …”

O data, where art thou? Revolutionizing data sharing to advance our sustainability goals through smart chemical innovation

“…The above example of effective peer-to-peer sharing does not circumvent the need for a data-sharing platform. Indeed, the outcomes of our study were eventually shared with the broader scientific community in a peer-reviewed publication ( Graham et al., 2022 ). As noted previously, the lack of a universal standard for (meta) data sharing in journals limits further usability of said data.…”

“…Our recent collaboration with pharmaceutical chemists and toxicologists to improve predictive models for peptide couplers, a unique class of dermal sensitizers, is a timely example of the value gained by overcoming resistance to sharing prized data and information ( Graham et al., 2022 ). In this case, mutual willingness of pharmaceutical companies and model developers to collaborate, where proprietary structures and expert knowledge were on the line, yielded better understanding of the underlying biochemistry; improved predictive models; and provided clues for the design of more benign future analogs ( Graham et al., 2022 ). With intellectual property at stake, our collaboration was made possible by advances in data-sharing technologies ( Farrall et al., 2021 ), which facilitated safe and secure data transfers to protect competitiveness and privacy of the involved parties.…”