How Direct Peptides Can Be Used to Identify Chemical Sensitisers


Direct peptides are a class of biologically active molecules that form covalent bonds between the thiol groups of two cysteine residues within a protein. In the human body they play a pivotal role in the regulation of hormone production and action. This article describes how these molecules can be used to identify chemical sensitisers by forming adducts with a cysteine-based peptide, and shows how a combination of the DPRA (direct peptide reactivity assay) and kDPRA (kinetic direct peptide reactivity assay) predictions, together with predictions from two in vitro cell-based assays, provide an overall prediction of whether chemicals are likely to be sensitisers or non-sensitisers, based on their electrophilic reactivity to a cysteine-based peptide.

The DPRA is an OECD test guideline method that uses the detection of adduct formation to determine if a chemical is likely to be a skin sensitiser (OECD 2021a). The kDPRA, which was developed more recently, involves incubating a mixture of chemicals with the cysteine-based peptide over a range of concentrations and incubation times to produce a data matrix of DP values, which are mathematically analysed to give a reactivity parameter logkmax that assigns chemicals to the 1A potency class if it is greater than -2.

Both the DPRA and the kDPRA have limitations. One issue is the fact that they rely on the implicit assumption that a chemical’s potency is simply a linear function of its reactivity and nothing else. This assumption is incorrect, as demonstrated by the results of our experiments with trimellitic and phthalic anhydrides, which are very similar in their reactivity to the peptide but have significantly different peptides uk

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