Abstract
The molecular chaperone Hsp90 is a ubiquitous ATPase-directed protein responsible for the activation and structural stabilization of a large clientele of proteins. As such, Hsp90 has emerged as a suitable candidate for the treatment of a diverse set of diseases, such as cancer and neurodegeneration. The inhibition of the chaperone through ATP-competitive inhibitors, however, was shown to lead to undesirable side effects. One strategy to alleviate this problem is the development of molecules that are able to disrupt specific protein–protein interactions, thus modulating the activity of Hsp90 only in the particular cellular pathway that needs to be targeted. Here, we exploit novel computational and theoretical approaches to design a set of peptides that are able to bind Hsp90 and compete for its interaction with the co-chaperone Cdc37, which is found to be responsible for the promotion of cancer cell proliferation. In spite of their capability to disrupt the Hsp90–Cdc37 interaction, no important cytotoxicity was observed in human cancer cells exposed to designed compounds. These findings imply the need for further optimization of the compounds, which may lead to new ways of interfering with the Hsp90 mechanisms that are important for tumour growth.
Highlights
Cellular homeostasis is a fine-tuned regulated condition, strictly dependent on the correct assembly and functionality of the proteome
Extensive middle domain (MD) simulations of 12 μs of the Heat Shock Protein 90 (Hsp90)/Cdk4/Cdc37 complex revealed that Hsp90 and
Cdc37 interact through a stable hydrogen bonding network established between two contact points, involving residues Y4-D15 and L119-N130 of Cdc37 (Table 1)
Summary
Cellular homeostasis is a fine-tuned regulated condition, strictly dependent on the correct assembly and functionality of the proteome. N-terminal-directed inhibitors tend to induce a heat shock response by activating HSF1, eventually resulting in an overexpression of the Hsp pathway, which ends up favouring cancer cell survival [14] For these reasons, alternative strategies leading to selective and more specific inhibition of Hsp are highly desirable [15,16,17,18]. The release in 2016 of the Cryo-EM structure of the Hsp90/Cdk4/Cdc complex can represent a major breakthrough, allowing—for the first time—the observation of the complete arrangement and interaction of Hsp with a client and its co-chaperone [19] This is of crucial importance to understand the mechanism of chaperone–client recognition and Hsp90-induced client maturation, and for drug development. The peptide sequences that scored favorably were designed and tested in Co-IP experiments to show their ability to disrupt Hsp complexes and impact on the maturation and cell levels of kinase clients
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