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J Med Chem. 2019 Jul 11;62(13):6377-6390. doi: 10.1021/acs.jmedchem.9b00878. Epub 2019 Jun 26.

De Novo Design of Boron-Based Peptidomimetics as Potent Inhibitors of Human ClpP in the Presence of Human ClpX.

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Davenport Research Laboratories, Department of Chemistry , University of Toronto , 80 St. George Street , Toronto , Ontario M5S 3H6 , Canada.
Drug Discovery Program , Ontario Institute for Cancer Research, MaRS Centre , 661 University Avenue , Suite 510 , Toronto , Ontario M5G 0A3 , Canada.
Princess Margaret Cancer Centre , University Health Network , 610 University Avenue , Toronto , Ontario M5G 2M9 , Canada.
Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , 262 Danny Thomas Place , Memphis , Tennessee 38105-3678 , United States.
Leslie Dan Faculty of Pharmacy , University of Toronto , 144 College Street , Toronto , Ontario M5S 3M2 , Canada.


Boronic acids have attracted the attention of synthetic and medicinal chemists due to boron's ability to modulate enzyme function. Recently, we demonstrated that boron-containing amphoteric building blocks facilitate the discovery of bioactive aminoboronic acids. Herein, we have augmented this capability with a de novo library design and a virtual screening platform modified for covalent ligands. This technique has allowed us to rapidly design and identify a series of α-aminoboronic acids as the first inhibitors of human ClpXP, which is responsible for the degradation of misfolded proteins.

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