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Assessment of Biological Role and Insight into Druggability of the Plasmodium falciparum Protease Plasmepsin V
[Image: see text] Upon infecting a red blood cell (RBC), the malaria parasite Plasmodium falciparum drastically remodels its host by exporting hundreds of proteins into the RBC cytosol. This protein export program is essential for parasite survival. Hence export-related proteins could be potential d...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155168/ https://www.ncbi.nlm.nih.gov/pubmed/32069391 http://dx.doi.org/10.1021/acsinfecdis.9b00460 |
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author | Polino, Alexander J. Nasamu, Armiyaw S. Niles, Jacquin C. Goldberg, Daniel E. |
author_facet | Polino, Alexander J. Nasamu, Armiyaw S. Niles, Jacquin C. Goldberg, Daniel E. |
author_sort | Polino, Alexander J. |
collection | PubMed |
description | [Image: see text] Upon infecting a red blood cell (RBC), the malaria parasite Plasmodium falciparum drastically remodels its host by exporting hundreds of proteins into the RBC cytosol. This protein export program is essential for parasite survival. Hence export-related proteins could be potential drug targets. One essential enzyme in this pathway is plasmepsin V (PMV), an aspartic protease that processes export-destined proteins in the parasite endoplasmic reticulum (ER) at the Plasmodium export element (PEXEL) motif. Despite long-standing interest in this enzyme, functional studies have been hindered by the inability of previous technologies to produce a regulatable lethal depletion of PMV. To overcome this technical barrier, we designed a system for stringent post-transcriptional regulation allowing a tightly controlled, tunable knockdown of PMV. Using this system, we found that PMV must be dramatically depleted to affect parasite growth, suggesting the parasite maintains this enzyme in substantial excess. Surprisingly, depletion of PMV arrested parasite growth immediately after RBC invasion, significantly before the death from exported protein deficit that has previously been described. The data suggest that PMV inhibitors can halt parasite growth at two distinct points in the parasite life cycle. However, overcoming the functional excess of PMV in the parasite may require inhibitor concentrations far beyond the enzyme’s IC(50). |
format | Online Article Text |
id | pubmed-7155168 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-71551682020-04-14 Assessment of Biological Role and Insight into Druggability of the Plasmodium falciparum Protease Plasmepsin V Polino, Alexander J. Nasamu, Armiyaw S. Niles, Jacquin C. Goldberg, Daniel E. ACS Infect Dis [Image: see text] Upon infecting a red blood cell (RBC), the malaria parasite Plasmodium falciparum drastically remodels its host by exporting hundreds of proteins into the RBC cytosol. This protein export program is essential for parasite survival. Hence export-related proteins could be potential drug targets. One essential enzyme in this pathway is plasmepsin V (PMV), an aspartic protease that processes export-destined proteins in the parasite endoplasmic reticulum (ER) at the Plasmodium export element (PEXEL) motif. Despite long-standing interest in this enzyme, functional studies have been hindered by the inability of previous technologies to produce a regulatable lethal depletion of PMV. To overcome this technical barrier, we designed a system for stringent post-transcriptional regulation allowing a tightly controlled, tunable knockdown of PMV. Using this system, we found that PMV must be dramatically depleted to affect parasite growth, suggesting the parasite maintains this enzyme in substantial excess. Surprisingly, depletion of PMV arrested parasite growth immediately after RBC invasion, significantly before the death from exported protein deficit that has previously been described. The data suggest that PMV inhibitors can halt parasite growth at two distinct points in the parasite life cycle. However, overcoming the functional excess of PMV in the parasite may require inhibitor concentrations far beyond the enzyme’s IC(50). American Chemical Society 2020-02-18 2020-04-10 /pmc/articles/PMC7155168/ /pubmed/32069391 http://dx.doi.org/10.1021/acsinfecdis.9b00460 Text en Copyright © 2020 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Polino, Alexander J. Nasamu, Armiyaw S. Niles, Jacquin C. Goldberg, Daniel E. Assessment of Biological Role and Insight into Druggability of the Plasmodium falciparum Protease Plasmepsin V |
title | Assessment of Biological Role and Insight into Druggability
of the Plasmodium falciparum Protease Plasmepsin
V |
title_full | Assessment of Biological Role and Insight into Druggability
of the Plasmodium falciparum Protease Plasmepsin
V |
title_fullStr | Assessment of Biological Role and Insight into Druggability
of the Plasmodium falciparum Protease Plasmepsin
V |
title_full_unstemmed | Assessment of Biological Role and Insight into Druggability
of the Plasmodium falciparum Protease Plasmepsin
V |
title_short | Assessment of Biological Role and Insight into Druggability
of the Plasmodium falciparum Protease Plasmepsin
V |
title_sort | assessment of biological role and insight into druggability
of the plasmodium falciparum protease plasmepsin
v |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155168/ https://www.ncbi.nlm.nih.gov/pubmed/32069391 http://dx.doi.org/10.1021/acsinfecdis.9b00460 |
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