CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)

Detalhes bibliográficos
Autor(a) principal: Debnath, Anjan
Data de Publicação: 2017
Outros Autores: Calvet, Claudia M., Jennings, Gareth, Zhou, Wenxu, Aksenov, Alexander, Luth, Madeline R., Abagyan, Ruben, Nes, W. David, McKerrow, James H., Podust, Larissa M.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/29537
Resumo: University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic Diseases. San Diego, CA, USA.
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spelling Debnath, AnjanCalvet, Claudia M.Jennings, GarethZhou, WenxuAksenov, AlexanderLuth, Madeline R.Abagyan, RubenNes, W. DavidMcKerrow, James H.Podust, Larissa M.2018-10-11T16:33:45Z2018-10-11T16:33:45Z2017DEBNATH, Anjan et al. CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). PLoS Neglected Tropical Diseases, v. 11, n. 12, p. 1-24, 28 Dec. 2017.1935-2727https://www.arca.fiocruz.br/handle/icict/2953710.1371/journal.pntd.00061041935-2735engPublic Library of ScienceCYP51Meningoencefalite amebiana primáriaTratamentoNaegleria fowleriSterolsPrimary amoebic meningoencephalitisDrug therapyAmoebasBiosynthesisTrophozoitesLipidsCYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleUniversity of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic Diseases. San Diego, CA, USA.University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic Diseases. San Diego, CA, USA. / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic Diseases. San Diego, CA, USA.Texas Tech University. Department of Chemistry & Biochemistry. Lubbock, TX, USA.University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic Diseases. San Diego, CA, USA.University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic Diseases. San Diego, CA, USA.University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic Diseases. San Diego, CA, USA.Texas Tech University. Department of Chemistry & Biochemistry. Lubbock, TX, USA.University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic Diseases. San Diego, CA, USA.University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic Diseases. San Diego, CA, USA.Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered “rare” (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug ‘repurposing’—a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially ‘druggable’ target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/29537/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALclaudiaM_calvet_etal_IOC.2017.pdfclaudiaM_calvet_etal_IOC.2017.pdfapplication/pdf8960746https://www.arca.fiocruz.br/bitstream/icict/29537/2/claudiaM_calvet_etal_IOC.2017.pdf34e63807d8ac54b41ce490f99289ba6eMD52TEXTclaudiaM_calvet_etal_IOC.2017.pdf.txtclaudiaM_calvet_etal_IOC.2017.pdf.txtExtracted texttext/plain77328https://www.arca.fiocruz.br/bitstream/icict/29537/3/claudiaM_calvet_etal_IOC.2017.pdf.txtd28669d2133926af95d89c095c6161a2MD53icict/295372023-09-04 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dc.title.en_US.fl_str_mv CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)
title CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)
spellingShingle CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)
Debnath, Anjan
CYP51
Meningoencefalite amebiana primária
Tratamento
Naegleria fowleri
Sterols
Primary amoebic meningoencephalitis
Drug therapy
Amoebas
Biosynthesis
Trophozoites
Lipids
title_short CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)
title_full CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)
title_fullStr CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)
title_full_unstemmed CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)
title_sort CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)
author Debnath, Anjan
author_facet Debnath, Anjan
Calvet, Claudia M.
Jennings, Gareth
Zhou, Wenxu
Aksenov, Alexander
Luth, Madeline R.
Abagyan, Ruben
Nes, W. David
McKerrow, James H.
Podust, Larissa M.
author_role author
author2 Calvet, Claudia M.
Jennings, Gareth
Zhou, Wenxu
Aksenov, Alexander
Luth, Madeline R.
Abagyan, Ruben
Nes, W. David
McKerrow, James H.
Podust, Larissa M.
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Debnath, Anjan
Calvet, Claudia M.
Jennings, Gareth
Zhou, Wenxu
Aksenov, Alexander
Luth, Madeline R.
Abagyan, Ruben
Nes, W. David
McKerrow, James H.
Podust, Larissa M.
dc.subject.other.pt_BR.fl_str_mv CYP51
Meningoencefalite amebiana primária
Tratamento
topic CYP51
Meningoencefalite amebiana primária
Tratamento
Naegleria fowleri
Sterols
Primary amoebic meningoencephalitis
Drug therapy
Amoebas
Biosynthesis
Trophozoites
Lipids
dc.subject.en.en_US.fl_str_mv Naegleria fowleri
Sterols
Primary amoebic meningoencephalitis
Drug therapy
Amoebas
Biosynthesis
Trophozoites
Lipids
description University of California. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic Diseases. San Diego, CA, USA.
publishDate 2017
dc.date.issued.fl_str_mv 2017
dc.date.accessioned.fl_str_mv 2018-10-11T16:33:45Z
dc.date.available.fl_str_mv 2018-10-11T16:33:45Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv DEBNATH, Anjan et al. CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). PLoS Neglected Tropical Diseases, v. 11, n. 12, p. 1-24, 28 Dec. 2017.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/29537
dc.identifier.issn.en_US.fl_str_mv 1935-2727
dc.identifier.doi.en_US.fl_str_mv 10.1371/journal.pntd.0006104
dc.identifier.eissn.en_US.fl_str_mv 1935-2735
identifier_str_mv DEBNATH, Anjan et al. CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). PLoS Neglected Tropical Diseases, v. 11, n. 12, p. 1-24, 28 Dec. 2017.
1935-2727
10.1371/journal.pntd.0006104
1935-2735
url https://www.arca.fiocruz.br/handle/icict/29537
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
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