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...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2021-01-01
|
Series: | PLoS ONE |
Online Access: | https://doi.org/10.1371/journal.pone.0241738 |
id |
doaj-23d070499b154d11aa93fd5498f6c574 |
---|---|
record_format |
Article |
spelling |
doaj-23d070499b154d11aa93fd5498f6c5742021-04-09T04:30:38ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01163e024173810.1371/journal.pone.0241738Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba.Logan TilleryKayleigh BarrettJenna GoldsteinJared W LassnerBram OsterhoutNathan L TranLily XuRyan M YoungJustin CraigIan ChunDavid M DranowJan AbendrothSilvia L DelkerDouglas R DaviesStephen J MayclinBrandy CalhounMadison J BolejackBart StakerSandhya SubramanianIsabelle PhanDonald D LorimerPeter J MylerThomas E EdwardsDennis E KyleChristopher A RiceJames C MorrisJames W LeahyRoman ManetschLynn K BarrettCraig L SmithWesley C Van VoorhisNaegleria 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.https://doi.org/10.1371/journal.pone.0241738 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Logan Tillery Kayleigh Barrett Jenna Goldstein Jared W Lassner Bram Osterhout Nathan L Tran Lily Xu Ryan M Young Justin Craig Ian Chun David M Dranow Jan Abendroth Silvia L Delker Douglas R Davies Stephen J Mayclin Brandy Calhoun Madison J Bolejack Bart Staker Sandhya Subramanian Isabelle Phan Donald D Lorimer Peter J Myler Thomas E Edwards Dennis E Kyle Christopher A Rice James C Morris James W Leahy Roman Manetsch Lynn K Barrett Craig L Smith Wesley C Van Voorhis |
spellingShingle |
Logan Tillery Kayleigh Barrett Jenna Goldstein Jared W Lassner Bram Osterhout Nathan L Tran Lily Xu Ryan M Young Justin Craig Ian Chun David M Dranow Jan Abendroth Silvia L Delker Douglas R Davies Stephen J Mayclin Brandy Calhoun Madison J Bolejack Bart Staker Sandhya Subramanian Isabelle Phan Donald D Lorimer Peter J Myler Thomas E Edwards Dennis E Kyle Christopher A Rice James C Morris James W Leahy Roman Manetsch Lynn K Barrett Craig L Smith Wesley C Van Voorhis Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba. PLoS ONE |
author_facet |
Logan Tillery Kayleigh Barrett Jenna Goldstein Jared W Lassner Bram Osterhout Nathan L Tran Lily Xu Ryan M Young Justin Craig Ian Chun David M Dranow Jan Abendroth Silvia L Delker Douglas R Davies Stephen J Mayclin Brandy Calhoun Madison J Bolejack Bart Staker Sandhya Subramanian Isabelle Phan Donald D Lorimer Peter J Myler Thomas E Edwards Dennis E Kyle Christopher A Rice James C Morris James W Leahy Roman Manetsch Lynn K Barrett Craig L Smith Wesley C Van Voorhis |
author_sort |
Logan Tillery |
title |
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_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_sort |
naegleria fowleri: protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2021-01-01 |
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. |
url |
https://doi.org/10.1371/journal.pone.0241738 |
work_keys_str_mv |
AT logantillery naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT kayleighbarrett naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT jennagoldstein naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT jaredwlassner naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT bramosterhout naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT nathanltran naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT lilyxu naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT ryanmyoung naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT justincraig naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT ianchun naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT davidmdranow naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT janabendroth naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT silvialdelker naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT douglasrdavies naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT stephenjmayclin naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT brandycalhoun naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT madisonjbolejack naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT bartstaker naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT sandhyasubramanian naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT isabellephan naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT donalddlorimer naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT peterjmyler naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT thomaseedwards naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT dennisekyle naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT christopherarice naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT jamescmorris naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT jameswleahy naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT romanmanetsch naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT lynnkbarrett naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT craiglsmith naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba AT wesleycvanvoorhis naegleriafowleriproteinstructurestofacilitatedrugdiscoveryforthedeadlypathogenicfreelivingamoeba |
_version_ |
1714685929892872192 |