Tailored Ahp‐cyclodepsipeptides as Potent Non‐covalent Serine Protease Inhibitors

The S1 serine protease family is one of the largest and most biologically important protease families. Despite their biomedical significance, generic approaches to generate potent, class‐specific, bioactive non‐covalent inhibitors for these enzymes are still limited. In this work, we demonstrate that Ahp‐cyclodepsipeptides represent a suitable scaffold for generating target‐tailored inhibitors of serine proteases. For efficient synthetic access, we developed a practical mixed solid‐ and solution‐phase synthesis that we validated through performing the first chemical synthesis of the two natural products Tasipeptin A and B. The suitability of the Ahp‐cyclodepsipeptide scaffold for tailored inhibitor synthesis is showcased by the generation of the most potent human HTRA protease inhibitors to date. We anticipate that our approach may also be applied to other serine proteases, thus opening new avenues for a systematic discovery of serine protease inhibitors. Made to measure: Ahp‐cyclodepsipeptides, a class of natural products with specific non‐covalent serine protease inhibitory properties, were tailored to generate potent chemical tools for investigating the biomedically relevant human HTRA proteases.