Design and biological testing of peptidic dimerization inhibitors of human Hsp90 that target the C-terminal domain

Biochimica Et Biophysica Acta
Bertan BoppJoachim Jose

Abstract

Small molecules targeting the dimerization interface of the C-terminal domain of Hsp90, a validated target for cancer treatment, have yet to be identified. Three peptides were designed with the aim to inhibit the dimerization of Hsp90. Computational and biophysical methods examined the α-helical structure for the three peptides. Based on the Autodisplay technology, a novel flow cytometer dimerization assay was developed to test inhibition of Hsp90 dimerization. Microscale thermophoresis was used to determine the K(D) of the peptides towards the C-terminal domain of Hsp90. MD simulations and CD spectroscopy indicated an α-helical structure for two of the three peptides. By flow cytometer analysis, IC(50) values of 2.08 μM for peptide H2 and 8.96 μM for peptide H3 were determined. Dimer formation of the C-terminal dimerization domain was analyzed by microscale thermophoresis, and a K(D) of 1.29 nM was determined. Furthermore, microscale thermophoresis studies demonstrated a high affinity binding of H2 and H3 to the C-terminal domain, with a K(D) of 1.02 μM and 1.46 μM, respectively. These results revealed the first peptidic inhibitors of Hsp90 dimerization targeting the C-terminal domain. Furthermore, it has been shown that these...Continue Reading

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Citations

Oct 11, 2017·Expert Review of Proteomics·Lorenz WeidenauerManfredo R Quadroni
Nov 25, 2018·ChemMedChem·Evamarie Hey-HawkinsDanijelа Maksimovic-Ivanic
Apr 13, 2017·Biotechnology and Bioengineering·Jan SchüürmannJoachim Jose
Jul 27, 2018·Journal of Medicinal Chemistry·Mariarosaria FerraroGiorgio Colombo

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