Cargando…

Design of Disruptors of the Hsp90–Cdc37 Interface

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....

Descripción completa

Detalles Bibliográficos
Autores principales: D’Annessa, Ilda, Hurwitz, Naama, Pirota, Valentina, Beretta, Giovanni Luca, Tinelli, Stella, Woodford, Mark, Freccero, Mauro, Mollapour, Mehdi, Zaffaroni, Nadia, Wolfson, Haim, Colombo, Giorgio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024268/
https://www.ncbi.nlm.nih.gov/pubmed/31952296
http://dx.doi.org/10.3390/molecules25020360
_version_ 1783498396070313984
author D’Annessa, Ilda
Hurwitz, Naama
Pirota, Valentina
Beretta, Giovanni Luca
Tinelli, Stella
Woodford, Mark
Freccero, Mauro
Mollapour, Mehdi
Zaffaroni, Nadia
Wolfson, Haim
Colombo, Giorgio
author_facet D’Annessa, Ilda
Hurwitz, Naama
Pirota, Valentina
Beretta, Giovanni Luca
Tinelli, Stella
Woodford, Mark
Freccero, Mauro
Mollapour, Mehdi
Zaffaroni, Nadia
Wolfson, Haim
Colombo, Giorgio
author_sort D’Annessa, Ilda
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7024268
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-70242682020-03-11 Design of Disruptors of the Hsp90–Cdc37 Interface D’Annessa, Ilda Hurwitz, Naama Pirota, Valentina Beretta, Giovanni Luca Tinelli, Stella Woodford, Mark Freccero, Mauro Mollapour, Mehdi Zaffaroni, Nadia Wolfson, Haim Colombo, Giorgio Molecules Article 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. MDPI 2020-01-15 /pmc/articles/PMC7024268/ /pubmed/31952296 http://dx.doi.org/10.3390/molecules25020360 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
D’Annessa, Ilda
Hurwitz, Naama
Pirota, Valentina
Beretta, Giovanni Luca
Tinelli, Stella
Woodford, Mark
Freccero, Mauro
Mollapour, Mehdi
Zaffaroni, Nadia
Wolfson, Haim
Colombo, Giorgio
Design of Disruptors of the Hsp90–Cdc37 Interface
title Design of Disruptors of the Hsp90–Cdc37 Interface
title_full Design of Disruptors of the Hsp90–Cdc37 Interface
title_fullStr Design of Disruptors of the Hsp90–Cdc37 Interface
title_full_unstemmed Design of Disruptors of the Hsp90–Cdc37 Interface
title_short Design of Disruptors of the Hsp90–Cdc37 Interface
title_sort design of disruptors of the hsp90–cdc37 interface
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024268/
https://www.ncbi.nlm.nih.gov/pubmed/31952296
http://dx.doi.org/10.3390/molecules25020360
work_keys_str_mv AT dannessailda designofdisruptorsofthehsp90cdc37interface
AT hurwitznaama designofdisruptorsofthehsp90cdc37interface
AT pirotavalentina designofdisruptorsofthehsp90cdc37interface
AT berettagiovanniluca designofdisruptorsofthehsp90cdc37interface
AT tinellistella designofdisruptorsofthehsp90cdc37interface
AT woodfordmark designofdisruptorsofthehsp90cdc37interface
AT frecceromauro designofdisruptorsofthehsp90cdc37interface
AT mollapourmehdi designofdisruptorsofthehsp90cdc37interface
AT zaffaroninadia designofdisruptorsofthehsp90cdc37interface
AT wolfsonhaim designofdisruptorsofthehsp90cdc37interface
AT colombogiorgio designofdisruptorsofthehsp90cdc37interface