Bicyclic peptides emerge as next-generation therapeutics (ref. 1). We introduce peptide-bismuth bicycles as a new class of bicyclic peptides with fascinating properties (ref. 2). Similarly to previously used alkylating agents (ref. 3), bismuth(III) can link three cysteines residues in peptides and hence generate highly constrained bicyclic molecules. Peptide-bismuth bicycles form instantaneously at physiological pH and are stable in aqueous solution for many weeks. The technology is biocompatible, enabling in-situ access to constrained peptides in biochemical assays. We demonstrate this for two screening campaigns targeting viral proteases, revealing a new lead compound that displayed inhibition constants similar to the best inhibitors reported. Peptide-bismuth bicycles are much more active and proteolytically stable than their linear precursor peptides, rendering them excellent starting points for next-generation drug candidates.