Phenyl Esters Are Potent Inhibitors of Caseinolytic Protease P and Reveal a Stereogenic Switch for Deoligomerization

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2015
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Hackl, Mathias W.
Lakemeyer, Markus
Dahmen, Maria
Glaser, Manuel
Pahl, Axel
Lorenz-Baath, Katrin
Menzel, Thomas
Sievers, Sonja
Antes, Iris
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Caseinolytic protease P (ClpP) represents a central bacterial degradation machinery that is involved in cell homeostasis and pathogenicity. The functional role of ClpP has been studied by genetic knockouts and through the use of beta-lactones, which remain the only specific inhibitors of ClpP discovered to date. Beta-lactones have served as chemical tools to manipulate ClpP in several organisms; however, their potency, selectivity and stability is limited. Despite detailed structural insights into the composition and conformational flexibility of the ClpP active site, no rational efforts to design specific non-beta-lactone inhibitors have been reported to date. In this work, an unbiased screen of more than 137 000 compounds was used to identify five phenyl ester compounds as highly potent ClpP inhibitors that were selective for bacterial, but not human ClpP. The potency of phenyl esters largely exceeded that of beta-lactones in ClpP peptidase and protease inhibition assays and displayed unique target selectivity in living S. aureus cells. Analytical studies revealed that while phenyl esters are cleaved like native peptide substrates, they remain covalently trapped as acyl-enzyme intermediates in the active site. The synthesis of 36 derivatives and subsequent structure-activity relationship (SAR) studies provided insights into conserved structural elements that are important for inhibition potency and acylation reactivity. Moreover, the stereochemistry of a methyl-substituent at the alpha position to the ester, resembling amino acid side chains in peptide substrates, impacted ClpP complex stability, causing either dissociation into heptamers or retention of the tetradecameric state. Mechanistic insights into this intriguing stereo switch and the phenyl ester binding mode were obtained by molecular docking experiments.

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ISO 690HACKL, Mathias W., Markus LAKEMEYER, Maria DAHMEN, Manuel GLASER, Axel PAHL, Katrin LORENZ-BAATH, Thomas MENZEL, Sonja SIEVERS, Thomas BÖTTCHER, Iris ANTES, Herbert WALDMANN, Stephan A. SIEBER, 2015. Phenyl Esters Are Potent Inhibitors of Caseinolytic Protease P and Reveal a Stereogenic Switch for Deoligomerization. In: Journal of the American Chemical Society : JACS. 2015, 137(26), pp. 8475-8483. ISSN 0002-7863. eISSN 1520-5126. Available under: doi: 10.1021/jacs.5b03084
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@article{Hackl2015Pheny-31879,
  year={2015},
  doi={10.1021/jacs.5b03084},
  title={Phenyl Esters Are Potent Inhibitors of Caseinolytic Protease P and Reveal a Stereogenic Switch for Deoligomerization},
  number={26},
  volume={137},
  issn={0002-7863},
  journal={Journal of the American Chemical Society : JACS},
  pages={8475--8483},
  author={Hackl, Mathias W. and Lakemeyer, Markus and Dahmen, Maria and Glaser, Manuel and Pahl, Axel and Lorenz-Baath, Katrin and Menzel, Thomas and Sievers, Sonja and Böttcher, Thomas and Antes, Iris and Waldmann, Herbert and Sieber, Stephan A.}
}
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