Rational design, synthesis and structural characterization of peptides and peptidomimetics to target Hsp90/Cdc37 interaction for treating hepatocellular carcinoma

Surya Sukumaran, Mingdian Tan, Shulamit Fluss Ben-Uliel, Hui Zhang, Marta De Zotti, Mei Sze Chua, Samuel K. So, Nir Qvit

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Heat shock protein 90 (Hsp90) and cell division cycle 37 (Cdc37) work together as a molecular chaperone complex to regulate the activity of a multitude of client protein kinases. These kinases belong to a wide array of intracellular signaling networks that mediate multiple cellular processes including proliferation. As a result, Hsp90 and Cdc37 represent innovative therapeutic targets in various cancers (such as leukemia, multiple myeloma, and hepatocellular carcinoma (HCC)) in which their expression levels are elevated. Conventional small molecule Hsp90 inhibitors act by blocking the conserved adenosine triphosphate (ATP) binding site. However, by targeting less conserved sites in a more specific manner, peptides and peptidomimetics (modified peptides) hold potential as more efficacious and less toxic alternatives to the conventional small molecule inhibitors. Using a rational approach, we herein developed bioactive peptides targeting Hsp90/Cdc37 interaction. A six amino acid linear peptide derived from Cdc37, KTGDEK, was designed to target Hsp90. We used in silico computational docking to first define its mode of interaction, and binding orientation, and then conjugated the peptide with a cell penetrating peptide, TAT, and a fluorescent dye to confirm its ability to colocalize with Hsp90 in HCC cells. Based on the parent linear sequence, we developed a peptidomimetics library of pre-cyclic and cyclic derivatives. These peptidomimetics were evaluated for their binding affinity to Hsp90, and bioactivity in HCC cell lines. Among them, a pre-cyclic peptidomimetic demonstrates high binding affinity and bioactivity in HCC cells, causing reduced cell proliferation that is associated with induction of cell apoptosis, and down-regulation of phosphorylated MEK1/2. Overall, this generalized approach of rational design, structural optimization, and cellular validation of ‘drug-like’ peptidomimetics against Hsp90/Cdc37 offers a feasible and promising way to design novel therapeutic agents for malignancies and other diseases that are dependent on this molecular chaperone complex.

Original languageEnglish
Pages (from-to)3159-3172
Number of pages14
JournalComputational and Structural Biotechnology Journal
Volume21
DOIs
StatePublished - Jan 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Funding

This research was supported by a grant from the Binational Science Foundation (BSF) to S.K.S. and N.Q., and by the CJ Huang Foundation to M.S.C., M.T., and H.Z. The authors would like to thank Yoav Luxembourg for his generous support. We also wish to acknowledge the help rendered by Avraham Samson for helpful guidance in docking analysis, and Moshe Dessau for sharing his computational knowledge in Structural Biology. M.D.Z. gratefully acknowledges funding by the Italian Ministry of University and Research (PRIN Project 2020833Y75 ).

FundersFunder number
CJ Huang Foundation
United States-Israel Binational Science Foundation
Ministero dell’Istruzione, dell’Università e della Ricerca2020833Y75

    Keywords

    • Backbone cyclization
    • CD (Circular dichroism)
    • Cdc37 (cell division cycle 37)
    • Colocalization
    • Cyclic peptidomimetics
    • Field effect biosensing (FEB)
    • HCC (hepatocellular carcinoma)
    • Hsp90 (heat shock protein 90)
    • Peptide probes
    • Peptides
    • Peptidomimetics
    • Pre-cyclic peptidomimetics
    • Protein-protein interaction

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