Discovery and identification of Cdc37-derived peptides targeting the Hsp90–Cdc37 protein–protein interaction

Abstract

As an attractive anticancer target, the Hsp90 chaperone machine regulates a wide range of oncoproteins. Most of the Hsp90 inhibitors in clinical trials employ the same ATP blockage mechanism while little progress has been achieved with Hsp90–cochaperone complexes. Numerous protein kinases associate with the Hsp90–Cdc37 PPI, a potential target for the treatment of cancers, to implement folding and maturation. In order to explore the key residues of the Hsp90–Cdc37 binding interface for further design of peptide inhibitors, a combined strategy of molecular dynamics simulation and MM-PBSA analysis was performed. Subsequent design and identification of an eleven-residue peptide (Pep-1) directly derived from the Cdc37 binding interface was achieved to exhibit a 6.9 μM binding capacity and 3.0 μM ATPase inhibitory rate. This is the first evidence that a peptide inhibitor not only interferes with Hsp90 ATPase ability but also disrupts the Cdc37–Hsp90 PPI.