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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....
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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 |
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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 |
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