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Tailored Ahp‐cyclodepsipeptides as Potent Non‐covalent Serine Protease Inhibitors
Author(s) -
Köcher Steffen,
Rey Juliana,
Bongard Jens,
Tiaden André N.,
Meltzer Michael,
Richards Peter J.,
Ehrmann Michael,
Kaiser Markus
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201701771
Subject(s) - proteases , serine , serine protease , protease , chemistry , biochemistry , enzyme , computational biology , combinatorial chemistry , biology
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.