An Evaluation of the Occupational Health Hazards of Peptide Couplers - PubMed (original) (raw)

. 2022 Jun 20;35(6):1011-1022.

doi: 10.1021/acs.chemrestox.2c00031. Epub 2022 May 9.

Alejandra Trejo-Martin 2, Martyn L Chilton 3, Jakub Kostal 4, Joel Bercu 2, Gregory L Beutner 5, Uma S Bruen 6, David G Dolan 7, Stephen Gomez 8, Jedd Hillegass 5, John Nicolette 9, Matthew Schmitz 10

Affiliations

An Evaluation of the Occupational Health Hazards of Peptide Couplers

Jessica C Graham et al. Chem Res Toxicol. 2022.

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1

Figure 1

Subclasses of amide bond forming agents. The most common peptide couplers can be divided into five main subclasses, including amidiniums (amidinium salts), activated phosphorous(V) compounds (phosphonium salts), carbodiimides, activated triazines (activated heterocycles), and activated carbonyls.

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