However, there remain concerns about off-target effects, due to reaction of the covalent warhead with other proteins. Targeted covalent inhibitors (TCIs) address this by combining weakly electrophilic warheads with high affinity scaffolds which optimally position the reactive group to react at a target residue. Peptides make an ideal modality for the high affinity scaffold due to their tight binding affinities, high target selectivity and relative ease and low cost of synthesis. Having a comparably small size, they can be orally bioavailable, whilst still having a sufficiently large surface area to target relatively featureless protein interfaces with high specificity. Macrocyclisation of peptides confers additional benefits including high proteolytic stability and increased potency. Classically, covalent peptides are developed through addition of a warhead into a previously identified reversible binder or substrate analogue, requiring structural information or laboriously generated structure activity relationship information. Identifying a suitable site for warhead addition that enables efficient reaction without disrupting potent target binding is challenging. Additionally, in many cases neither a substrate analogue nor structural information is available. Addressing both these challenges, direct identification of covalent peptides from high-throughput screening offers a route to speed up covalent drug discovery.