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

Angewandte Chemie
Steffen KöcherMarkus Kaiser

Abstract

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.

References

Mar 1, 1995·Protein Science : a Publication of the Protein Society·J J Perona, C S Craik
Oct 1, 1993·The Journal of Antibiotics·C MartinJ Weckesser
Dec 12, 2002·Chemical Reviews·James C PowersKaren Ellis James
May 24, 2003·Journal of Natural Products·Philip G WilliamsValerie J Paul
Oct 30, 2003·Chemistry & Biology·Ute MaternGeorg E Schulz
Oct 23, 2004·Journal of Natural Products·Bojan BisterFriedrich Jüttner
Dec 27, 2005·The Journal of Biological Chemistry·Sandra GrauMichael Ehrmann
Feb 3, 2007·Journal of Proteome Research·Lieselotte Vande WallePeter Vandenabeele
Jan 1, 2008·Journal of Natural Products·Roger G LiningtonWilliam H Gerwick
Oct 17, 2008·Chembiochem : a European Journal of Chemical Biology·Christian MehnerGabriele M König
Sep 3, 2010·Nature Reviews. Drug Discovery·Marcin Drag, Guy S Salvesen
Feb 8, 2011·Nature Structural & Molecular Biology·Linda TruebesteinMichael Ehrmann
Feb 18, 2011·Nature Reviews. Molecular Cell Biology·Tim ClausenMichael Ehrmann
Jun 7, 2014·Angewandte Chemie·Krystle C H ChuaAndrew D Abell
Jun 7, 2014·Annual Review of Biochemistry·Laura E Sanman, Matthew Bogyo
May 23, 2015·Chembiochem : a European Journal of Chemical Biology·Agata GitlinKrzysztof Rolka
Jul 15, 2015·Biochimie·Eliane V Wolf, Steven H L Verhelst
Oct 6, 2015·Nature Chemical Biology·Simon PoepselMichael Ehrmann
Jan 24, 2017·Investigative Ophthalmology & Visual Science·Gian Marco TosiFederico Galvagni

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Citations

Jan 11, 2020·Acta Crystallographica. Section C, Structural Chemistry·Anthony LindenHeinz Heimgartner
Jun 11, 2020·Natural Product Reports·Fatma H Al-Awadhi, Hendrik Luesch
Apr 7, 2020·Chemistry : a European Journal·Daniel KrahnMarkus Kaiser
May 14, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lik Tong Tan, Ma Yadanar Phyo
May 1, 2021·International Journal of Molecular Sciences·Jia-Nan ZhangHong-Jie Zhang
Aug 14, 2020·ACS Chemical Biology·Ho Yeon NamJiyoun Lee

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