Bicyclic peptides are a powerful modality for engaging challenging drug targets such as protein-protein interactions. Here, we use 1,2,3-tris(bromomethyl) benzene (1,2,3-TBMB) to access bicyclic peptides with diverse conformations that differ from conventional bicyclisation products formed with 1,3,5-TBMB. Bicyclisation at cysteine residues under aqueous buffer conditions proceeds efficiently, with broad substrate scope, compatibility with high-throughput screening, and clean conversion (>90%) for 96 of the 115 peptides tested. We envisage the 1,2,3-TBMB linker will be applicable to a variety of peptide screening techniques in drug discovery.

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