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BacPROTACs mediate targeted protein degradation in bacteria

Francesca Ester Morreale, Stefan Kleine, Julia Leodolter, Stepan Ovchinnikov, Juliane Kley, Robert Kurzbauer, David M. Hoi, Anton Meinhart, Markus Hartl, David Haselbach, Markus Kaiser, View ORCID ProfileTim Clausen
doi: https://doi.org/10.1101/2021.06.09.447781
Francesca Ester Morreale
1Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
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Stefan Kleine
2University of Duisburg-Essen, Center of Medical Biotechnology, Faculty of Biology, Essen, Germany
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Julia Leodolter
1Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
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Stepan Ovchinnikov
1Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
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Juliane Kley
1Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
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Robert Kurzbauer
1Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
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David M. Hoi
1Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
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Anton Meinhart
1Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
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Markus Hartl
3Max Perutz Labs, Vienna BioCenter, Vienna, Austria
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David Haselbach
1Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
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Markus Kaiser
2University of Duisburg-Essen, Center of Medical Biotechnology, Faculty of Biology, Essen, Germany
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Tim Clausen
1Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
4Medical University of Vienna, Vienna, Austria
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  • ORCID record for Tim Clausen
  • For correspondence: tim.clausen@imp.ac.at
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Summary

Hijacking the cellular protein degradation system offers unique opportunities for drug discovery, as exemplified by proteolysis targeting chimeras (PROTACs). Despite their superior properties over classical inhibitors, it has so far not been possible to reprogram the bacterial degradation machinery to interfere with microbial infections. Here, we develop small-molecule degraders, so-called BacPROTACs, that bind to the substrate receptor of the ClpC:ClpP protease, priming neo-substrates for degradation. In addition to their targeting function, BacPROTACs activate ClpC, transforming the resting unfoldase into its functional state. The induced higher-order oligomer was visualized by cryo-EM analysis, providing a structural snapshot of activated ClpC unfolding a protein substrate. Finally, degradation assays performed in mycobacteria demonstrate in vivo activity of BacPROTACs, highlighting the potential of the technology to provide next generation antibiotics.

Competing Interest Statement

Authors F.E.M., S.K., J.L., A.M., M.K. and T.C. are named as inventors of a patent that is based on the presented findings.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 10, 2021.
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BacPROTACs mediate targeted protein degradation in bacteria
Francesca Ester Morreale, Stefan Kleine, Julia Leodolter, Stepan Ovchinnikov, Juliane Kley, Robert Kurzbauer, David M. Hoi, Anton Meinhart, Markus Hartl, David Haselbach, Markus Kaiser, Tim Clausen
bioRxiv 2021.06.09.447781; doi: https://doi.org/10.1101/2021.06.09.447781
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BacPROTACs mediate targeted protein degradation in bacteria
Francesca Ester Morreale, Stefan Kleine, Julia Leodolter, Stepan Ovchinnikov, Juliane Kley, Robert Kurzbauer, David M. Hoi, Anton Meinhart, Markus Hartl, David Haselbach, Markus Kaiser, Tim Clausen
bioRxiv 2021.06.09.447781; doi: https://doi.org/10.1101/2021.06.09.447781

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