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Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites
Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological conditions associated w...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929125/ https://www.ncbi.nlm.nih.gov/pubmed/31775392 http://dx.doi.org/10.3390/ijms20235930 |
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author | Zininga, Tawanda Shonhai, Addmore |
author_facet | Zininga, Tawanda Shonhai, Addmore |
author_sort | Zininga, Tawanda |
collection | PubMed |
description | Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological conditions associated with the human host and in the arthropod vectors requires the parasites to modulate their metabolic complement in order to meet the prevailing conditions. One of the key features of these parasites essential for their survival and host infectivity is timely expression of various proteins. Even more importantly is the need to keep their proteome functional by maintaining its functional capabilities in the wake of physiological changes and host immune responses. For this reason, molecular chaperones (also called heat shock proteins)—whose role is to facilitate proteostasis—play an important role in the survival of these parasites. Heat shock protein 90 (Hsp90) and Hsp70 are prominent molecular chaperones that are generally induced in response to physiological stress. Both Hsp90 and Hsp70 members are functionally regulated by nucleotides. In addition, Hsp70 and Hsp90 cooperate to facilitate folding of some key proteins implicated in cellular development. In addition, Hsp90 and Hsp70 individually interact with other accessory proteins (co-chaperones) that regulate their functions. The dependency of these proteins on nucleotide for their chaperone function presents an Achille’s heel, as inhibitors that mimic ATP are amongst potential therapeutic agents targeting their function in obligate intracellular human parasites. Most of the promising small molecule inhibitors of parasitic heat shock proteins are either antibiotics or anticancer agents, whose repurposing against parasitic infections holds prospects. Both cancer cells and obligate human parasites depend upon a robust protein quality control system to ensure their survival, and hence, both employ a competent heat shock machinery to this end. Furthermore, some inhibitors that target chaperone and co-chaperone networks also offer promising prospects as antiparasitic agents. The current review highlights the progress made so far in design and application of small molecule inhibitors against obligate intracellular human parasites of the kinetoplastida and apicomplexan kingdoms. |
format | Online Article Text |
id | pubmed-6929125 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69291252019-12-26 Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites Zininga, Tawanda Shonhai, Addmore Int J Mol Sci Review Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological conditions associated with the human host and in the arthropod vectors requires the parasites to modulate their metabolic complement in order to meet the prevailing conditions. One of the key features of these parasites essential for their survival and host infectivity is timely expression of various proteins. Even more importantly is the need to keep their proteome functional by maintaining its functional capabilities in the wake of physiological changes and host immune responses. For this reason, molecular chaperones (also called heat shock proteins)—whose role is to facilitate proteostasis—play an important role in the survival of these parasites. Heat shock protein 90 (Hsp90) and Hsp70 are prominent molecular chaperones that are generally induced in response to physiological stress. Both Hsp90 and Hsp70 members are functionally regulated by nucleotides. In addition, Hsp70 and Hsp90 cooperate to facilitate folding of some key proteins implicated in cellular development. In addition, Hsp90 and Hsp70 individually interact with other accessory proteins (co-chaperones) that regulate their functions. The dependency of these proteins on nucleotide for their chaperone function presents an Achille’s heel, as inhibitors that mimic ATP are amongst potential therapeutic agents targeting their function in obligate intracellular human parasites. Most of the promising small molecule inhibitors of parasitic heat shock proteins are either antibiotics or anticancer agents, whose repurposing against parasitic infections holds prospects. Both cancer cells and obligate human parasites depend upon a robust protein quality control system to ensure their survival, and hence, both employ a competent heat shock machinery to this end. Furthermore, some inhibitors that target chaperone and co-chaperone networks also offer promising prospects as antiparasitic agents. The current review highlights the progress made so far in design and application of small molecule inhibitors against obligate intracellular human parasites of the kinetoplastida and apicomplexan kingdoms. MDPI 2019-11-25 /pmc/articles/PMC6929125/ /pubmed/31775392 http://dx.doi.org/10.3390/ijms20235930 Text en © 2019 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 | Review Zininga, Tawanda Shonhai, Addmore Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites |
title | Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites |
title_full | Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites |
title_fullStr | Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites |
title_full_unstemmed | Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites |
title_short | Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites |
title_sort | small molecule inhibitors targeting the heat shock protein system of human obligate protozoan parasites |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929125/ https://www.ncbi.nlm.nih.gov/pubmed/31775392 http://dx.doi.org/10.3390/ijms20235930 |
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