Anaphylaxis induced by peptide coupling agents: Lessons learned from prolonged exposure to HATU, HBTU, and HCTU

Chemical sensitization causes an immune response in the form of reactions as mild as seasonal allergy symptoms (rhinitis) and as severe as dermatitis and anaphylaxis. Different classes of chemical sensitizers are known, and their shared mode of action is the ability to covalently modify human proteins. While chemicals that have the ability to covalently modify proteins should be treated as potential sensitizers, these compounds are generally not handled as such until a researcher becomes sensitized. Peptide coupling agents are a prime example. The carbodiimide-based peptide coupling agent, DCC, is a notorious chemical sensitizer, and twenty-three cases of DCC induced chemical sensitivity were reported between 1959 and 2007. DCC is therefore widely treated with high laboratory safety standards in mind. Uronium-based coupling agents HATU, HBTU, and HCTU were developed after DCC, and were originally thought to have less sensitizing ability. They were also desirable for use in peptide synthesis due to their efficiency in inducing the formation of peptide bonds. Between 2003 and 2010, nine cases of sensitization by uronium-based coupling agents HATU and/or HBTU were reported. However, uronium-based coupling agents are rarely handled in the lab as sensitizers due to a lack of widespread knowledge about their sensitization ability as well as lack of toxicity information on chemical material safety data sheets. We report a case of chemical sensitization occurring over the course of three years and resulting in anaphylaxis from all three uronium-based coupling agents; HATU, HBTU, and HCTU, and we include recommendations for sensitizer safe handling procedures in academic laboratories. We also discuss risk assessments that should be taken when handling chemicals that have the potential to modify human protein.