ADEP interacts with the human mitochondrial ClpP (HsClpP) and result in the dysregulated activation of the protease, causing it to degrade peptidyl and protein substrates in an uncontrolled manner. Structurally, binding of ADEP (shown here as blue spheres) to the HsClpP tetradecamer (HsClpP14) induces the structuring of its axial pore loops and widening of its axial pore, thereby allowing unregulated access of substrates into HsClpP’s proteolytic chamber. At the cellular level, ADEP-induced dysregulation of HsClpP induces cytotoxicity in HEK293 and several cancer model cell lines caused by the activation of intrinsic, caspase-dependent apoptosis. Shown here are 3DSIM images of HEK293 cells that have been treated with ADEP for 72 hours at the early stages of apoptosis, during which the mitochondrial network becomes fragmented.
Acyldepsipeptides (ADEPs) compounds have bactericidal properties via dysregulating the activity of the highly conserved tetradecameric bacterial ClpP protease. In a recent publication in Cell Chemical Biology, Keith S. Wong and co-authors from the Houry group have reported on the identification of ADEP analogs that are potent dysregulators of the human mitochondrial ClpP (HsClpP). These analogs interact with HsClpP at high affinity, causing the protease to non-specifically degrade model substrates. Furthermore, dysregulation of HsClpP activity by ADEP was found to induce cytotoxic effects resulted from the activation of intrinsic, caspase-dependent apoptosis. ADEP-HsClpP co-crystal structure was solved for one of the analogs, ADEP-41, which revealed a highly complementary binding interface formed by two HsClpP neighbouring subunits. Importantly, given that HsClpP is highly expressed in multiple cancers and has important roles in cell metastasis, our findings highlight the anti-cancer potential of ADEPs that supports their further development as cancer therapeutics.
