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Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba
Naegleria fowleri is a pathogenic, thermophilic, free-living amoeba which causes primary amebic meningoencephalitis (PAM). Penetrating the olfactory mucosa, the brain-eating amoeba travels along the olfactory nerves, burrowing through the cribriform plate to its destination: the brain’s frontal lobe...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990177/ https://www.ncbi.nlm.nih.gov/pubmed/33760815 http://dx.doi.org/10.1371/journal.pone.0241738 |
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author | Tillery, Logan Barrett, Kayleigh Goldstein, Jenna Lassner, Jared W. Osterhout, Bram Tran, Nathan L. Xu, Lily Young, Ryan M. Craig, Justin Chun, Ian Dranow, David M. Abendroth, Jan Delker, Silvia L. Davies, Douglas R. Mayclin, Stephen J. Calhoun, Brandy Bolejack, Madison J. Staker, Bart Subramanian, Sandhya Phan, Isabelle Lorimer, Donald D. Myler, Peter J. Edwards, Thomas E. Kyle, Dennis E. Rice, Christopher A. Morris, James C. Leahy, James W. Manetsch, Roman Barrett, Lynn K. Smith, Craig L. Van Voorhis, Wesley C. |
author_facet | Tillery, Logan Barrett, Kayleigh Goldstein, Jenna Lassner, Jared W. Osterhout, Bram Tran, Nathan L. Xu, Lily Young, Ryan M. Craig, Justin Chun, Ian Dranow, David M. Abendroth, Jan Delker, Silvia L. Davies, Douglas R. Mayclin, Stephen J. Calhoun, Brandy Bolejack, Madison J. Staker, Bart Subramanian, Sandhya Phan, Isabelle Lorimer, Donald D. Myler, Peter J. Edwards, Thomas E. Kyle, Dennis E. Rice, Christopher A. Morris, James C. Leahy, James W. Manetsch, Roman Barrett, Lynn K. Smith, Craig L. Van Voorhis, Wesley C. |
author_sort | Tillery, Logan |
collection | PubMed |
description | Naegleria fowleri is a pathogenic, thermophilic, free-living amoeba which causes primary amebic meningoencephalitis (PAM). Penetrating the olfactory mucosa, the brain-eating amoeba travels along the olfactory nerves, burrowing through the cribriform plate to its destination: the brain’s frontal lobes. The amoeba thrives in warm, freshwater environments, with peak infection rates in the summer months and has a mortality rate of approximately 97%. A major contributor to the pathogen’s high mortality is the lack of sensitivity of N. fowleri to current drug therapies, even in the face of combination-drug therapy. To enable rational drug discovery and design efforts we have pursued protein production and crystallography-based structure determination efforts for likely drug targets from N. fowleri. The genes were selected if they had homology to drug targets listed in Drug Bank or were nominated by primary investigators engaged in N. fowleri research. In 2017, 178 N. fowleri protein targets were queued to the Seattle Structural Genomics Center of Infectious Disease (SSGCID) pipeline, and to date 89 soluble recombinant proteins and 19 unique target structures have been produced. Many of the new protein structures are potential drug targets and contain structural differences compared to their human homologs, which could allow for the development of pathogen-specific inhibitors. Five of the structures were analyzed in more detail, and four of five show promise that selective inhibitors of the active site could be found. The 19 solved crystal structures build a foundation for future work in combating this devastating disease by encouraging further investigation to stimulate drug discovery for this neglected pathogen. |
format | Online Article Text |
id | pubmed-7990177 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-79901772021-04-05 Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba Tillery, Logan Barrett, Kayleigh Goldstein, Jenna Lassner, Jared W. Osterhout, Bram Tran, Nathan L. Xu, Lily Young, Ryan M. Craig, Justin Chun, Ian Dranow, David M. Abendroth, Jan Delker, Silvia L. Davies, Douglas R. Mayclin, Stephen J. Calhoun, Brandy Bolejack, Madison J. Staker, Bart Subramanian, Sandhya Phan, Isabelle Lorimer, Donald D. Myler, Peter J. Edwards, Thomas E. Kyle, Dennis E. Rice, Christopher A. Morris, James C. Leahy, James W. Manetsch, Roman Barrett, Lynn K. Smith, Craig L. Van Voorhis, Wesley C. PLoS One Research Article Naegleria fowleri is a pathogenic, thermophilic, free-living amoeba which causes primary amebic meningoencephalitis (PAM). Penetrating the olfactory mucosa, the brain-eating amoeba travels along the olfactory nerves, burrowing through the cribriform plate to its destination: the brain’s frontal lobes. The amoeba thrives in warm, freshwater environments, with peak infection rates in the summer months and has a mortality rate of approximately 97%. A major contributor to the pathogen’s high mortality is the lack of sensitivity of N. fowleri to current drug therapies, even in the face of combination-drug therapy. To enable rational drug discovery and design efforts we have pursued protein production and crystallography-based structure determination efforts for likely drug targets from N. fowleri. The genes were selected if they had homology to drug targets listed in Drug Bank or were nominated by primary investigators engaged in N. fowleri research. In 2017, 178 N. fowleri protein targets were queued to the Seattle Structural Genomics Center of Infectious Disease (SSGCID) pipeline, and to date 89 soluble recombinant proteins and 19 unique target structures have been produced. Many of the new protein structures are potential drug targets and contain structural differences compared to their human homologs, which could allow for the development of pathogen-specific inhibitors. Five of the structures were analyzed in more detail, and four of five show promise that selective inhibitors of the active site could be found. The 19 solved crystal structures build a foundation for future work in combating this devastating disease by encouraging further investigation to stimulate drug discovery for this neglected pathogen. Public Library of Science 2021-03-24 /pmc/articles/PMC7990177/ /pubmed/33760815 http://dx.doi.org/10.1371/journal.pone.0241738 Text en © 2021 Tillery et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Tillery, Logan Barrett, Kayleigh Goldstein, Jenna Lassner, Jared W. Osterhout, Bram Tran, Nathan L. Xu, Lily Young, Ryan M. Craig, Justin Chun, Ian Dranow, David M. Abendroth, Jan Delker, Silvia L. Davies, Douglas R. Mayclin, Stephen J. Calhoun, Brandy Bolejack, Madison J. Staker, Bart Subramanian, Sandhya Phan, Isabelle Lorimer, Donald D. Myler, Peter J. Edwards, Thomas E. Kyle, Dennis E. Rice, Christopher A. Morris, James C. Leahy, James W. Manetsch, Roman Barrett, Lynn K. Smith, Craig L. Van Voorhis, Wesley C. Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba |
title | Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba |
title_full | Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba |
title_fullStr | Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba |
title_full_unstemmed | Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba |
title_short | Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba |
title_sort | naegleria fowleri: protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990177/ https://www.ncbi.nlm.nih.gov/pubmed/33760815 http://dx.doi.org/10.1371/journal.pone.0241738 |
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