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

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.