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However, such efforts present a considerable challenge when one fragment binds covalently to the target protein, as small modifications can influence the correct positioning of the covalent warhead toward the targeted nucleophilic residue. Here, we present a case study of fragment linking that yielded single\u2010digit micromolar, covalent inhibitors of the SARS\u2010CoV\u20102 main protease, starting from fragments that were inactive in the biochemical assay. Using structural information from a recent, high\u2010throughput crystallographic fragment screen, we show that the success of fragment linking in the design of targeted covalent inhibitors is heavily impacted by several factors, including the warhead type, the labeling chemistry, and even subtle changes in the designed linker. 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