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Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules
Protozoan parasites are responsible for several harmful and widespread human diseases that cause high morbidity and mortality. Currently available treatments have serious limitations due to poor efficiency, strong adverse effects, and high cost. Hence, the identification of new targets and the devel...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9692773/ https://www.ncbi.nlm.nih.gov/pubmed/36355513 http://dx.doi.org/10.3390/ph15111341 |
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author | Tassone, Giusy Mazzorana, Marco Pozzi, Cecilia |
author_facet | Tassone, Giusy Mazzorana, Marco Pozzi, Cecilia |
author_sort | Tassone, Giusy |
collection | PubMed |
description | Protozoan parasites are responsible for several harmful and widespread human diseases that cause high morbidity and mortality. Currently available treatments have serious limitations due to poor efficiency, strong adverse effects, and high cost. Hence, the identification of new targets and the development of specific drug therapies against parasitic diseases are urgent needs. Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone that plays a key role in parasite survival during the various differentiation stages, spread over the vector insect and the human host, which they undergo during their life cycle. The N-terminal domain (NTD) of HSP90, containing the main determinants for ATPase activity, represents the most druggable domain for inhibitor targeting. The molecules investigated on parasite HSP90 are mainly developed from known inhibitors of the human counterpart, and they have strong limitations due to selectivity issues, accounting for the high conservation of the ATP-binding site between the parasite and human proteins. The current review highlights the recent structural progress made to support the rational design of new molecules able to effectively block the chaperone activity of parasite HSP90. |
format | Online Article Text |
id | pubmed-9692773 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96927732022-11-26 Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules Tassone, Giusy Mazzorana, Marco Pozzi, Cecilia Pharmaceuticals (Basel) Review Protozoan parasites are responsible for several harmful and widespread human diseases that cause high morbidity and mortality. Currently available treatments have serious limitations due to poor efficiency, strong adverse effects, and high cost. Hence, the identification of new targets and the development of specific drug therapies against parasitic diseases are urgent needs. Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone that plays a key role in parasite survival during the various differentiation stages, spread over the vector insect and the human host, which they undergo during their life cycle. The N-terminal domain (NTD) of HSP90, containing the main determinants for ATPase activity, represents the most druggable domain for inhibitor targeting. The molecules investigated on parasite HSP90 are mainly developed from known inhibitors of the human counterpart, and they have strong limitations due to selectivity issues, accounting for the high conservation of the ATP-binding site between the parasite and human proteins. The current review highlights the recent structural progress made to support the rational design of new molecules able to effectively block the chaperone activity of parasite HSP90. MDPI 2022-10-29 /pmc/articles/PMC9692773/ /pubmed/36355513 http://dx.doi.org/10.3390/ph15111341 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Tassone, Giusy Mazzorana, Marco Pozzi, Cecilia Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules |
title | Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules |
title_full | Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules |
title_fullStr | Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules |
title_full_unstemmed | Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules |
title_short | Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules |
title_sort | structural basis of parasitic hsp90 atpase inhibition by small molecules |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9692773/ https://www.ncbi.nlm.nih.gov/pubmed/36355513 http://dx.doi.org/10.3390/ph15111341 |
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