Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity

Detalhes bibliográficos
Autor(a) principal: Tavella, Tatyana Almeida
Data de Publicação: 2021
Outros Autores: Da Silva, Noeli Soares Melo, Spillman, Natalie, Kayano, Ana Carolina Andrade Vitor, Cassiano, Gustavo Capatti, Vasconcelos, Adrielle Ayumi, Camargo, Antônio Pedro, Da Silva, Djane Clarys Baia, Fontinha, Diana, Salazar Alvarez, Luis Carlos, Ferreira, Letícia Tiburcio, Peralis Tomaz, Kaira Cristina, Neves, Bruno Junior, Almeida, Ludimila Dias, Bargieri, Daniel Youssef, Lacerda, Marcus Vinicius Guimarães De, Lemos Cravo, Pedro Vitor, Sunnerhagen, Per, Prudêncio, Miguel, Andrade, Carolina Horta, Pinto Lopes, Stefanie Costa, Carazzolle, Marcelo Falsarella, Tilley, Leann, Bilsland, Elizabeth, Borges, Júlio César, Maranhão Costa, Fabio Trindade
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10362/116523
Resumo: Antimalarial drugs with novel modes of action and wide therapeutic potential are needed to pave the way for malaria eradication. Violacein is a natural compound known for its biological activity against cancer cells and several pathogens, including the malaria parasite, Plasmodium falciparum (Pf). Herein, using chemical genomic profiling (CGP), we found that violacein affects protein homeostasis. Mechanistically, violacein binds Pf chaperones, PfHsp90 and PfHsp70-1, compromising the latter's ATPase and chaperone activities. Additionally, violacein-treated parasites exhibited increased protein unfolding and proteasomal degradation. The uncoupling of the parasite stress response reflects the multistage growth inhibitory effect promoted by violacein. Despite evidence of proteotoxic stress, violacein did not inhibit global protein synthesis via UPR activation - a process that is highly dependent on chaperones, in agreement with the notion of a violacein-induced proteostasis collapse. Our data highlight the importance of a functioning chaperone-proteasome system for parasite development and differentiation. Thus, a violacein-like small molecule might provide a good scaffold for development of a novel probe for examining the molecular chaperone network and/or antiplasmodial drug design.
id RCAP_32744e45f5d46ae4dab86e15307afe44
oai_identifier_str oai:run.unl.pt:10362/116523
network_acronym_str RCAP
network_name_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository_id_str 7160
spelling Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activitychaperone inhibitorchemogenomicsmalariaproteostasisviolaceinStructural BiologyInfectious DiseasesSDG 1 - No PovertySDG 3 - Good Health and Well-beingSDG 9 - Industry, Innovation, and InfrastructureAntimalarial drugs with novel modes of action and wide therapeutic potential are needed to pave the way for malaria eradication. Violacein is a natural compound known for its biological activity against cancer cells and several pathogens, including the malaria parasite, Plasmodium falciparum (Pf). Herein, using chemical genomic profiling (CGP), we found that violacein affects protein homeostasis. Mechanistically, violacein binds Pf chaperones, PfHsp90 and PfHsp70-1, compromising the latter's ATPase and chaperone activities. Additionally, violacein-treated parasites exhibited increased protein unfolding and proteasomal degradation. The uncoupling of the parasite stress response reflects the multistage growth inhibitory effect promoted by violacein. Despite evidence of proteotoxic stress, violacein did not inhibit global protein synthesis via UPR activation - a process that is highly dependent on chaperones, in agreement with the notion of a violacein-induced proteostasis collapse. Our data highlight the importance of a functioning chaperone-proteasome system for parasite development and differentiation. Thus, a violacein-like small molecule might provide a good scaffold for development of a novel probe for examining the molecular chaperone network and/or antiplasmodial drug design.Vector borne diseases and pathogens (VBD)Global Health and Tropical Medicine (GHTM)Instituto de Higiene e Medicina Tropical (IHMT)RUNTavella, Tatyana AlmeidaDa Silva, Noeli Soares MeloSpillman, NatalieKayano, Ana Carolina Andrade VitorCassiano, Gustavo CapattiVasconcelos, Adrielle AyumiCamargo, Antônio PedroDa Silva, Djane Clarys BaiaFontinha, DianaSalazar Alvarez, Luis CarlosFerreira, Letícia TiburcioPeralis Tomaz, Kaira CristinaNeves, Bruno JuniorAlmeida, Ludimila DiasBargieri, Daniel YoussefLacerda, Marcus Vinicius Guimarães DeLemos Cravo, Pedro VitorSunnerhagen, PerPrudêncio, MiguelAndrade, Carolina HortaPinto Lopes, Stefanie CostaCarazzolle, Marcelo FalsarellaTilley, LeannBilsland, ElizabethBorges, Júlio CésarMaranhão Costa, Fabio Trindade2021-04-30T22:44:37Z2021-03-102021-03-10T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article8application/pdfhttp://hdl.handle.net/10362/116523eng2373-8227PURE: 29207291https://doi.org/10.1021/acsinfecdis.0c00454info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-05-22T17:52:19Zoai:run.unl.pt:10362/116523Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-05-22T17:52:19Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
title Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
spellingShingle Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
Tavella, Tatyana Almeida
chaperone inhibitor
chemogenomics
malaria
proteostasis
violacein
Structural Biology
Infectious Diseases
SDG 1 - No Poverty
SDG 3 - Good Health and Well-being
SDG 9 - Industry, Innovation, and Infrastructure
title_short Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
title_full Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
title_fullStr Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
title_full_unstemmed Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
title_sort Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
author Tavella, Tatyana Almeida
author_facet Tavella, Tatyana Almeida
Da Silva, Noeli Soares Melo
Spillman, Natalie
Kayano, Ana Carolina Andrade Vitor
Cassiano, Gustavo Capatti
Vasconcelos, Adrielle Ayumi
Camargo, Antônio Pedro
Da Silva, Djane Clarys Baia
Fontinha, Diana
Salazar Alvarez, Luis Carlos
Ferreira, Letícia Tiburcio
Peralis Tomaz, Kaira Cristina
Neves, Bruno Junior
Almeida, Ludimila Dias
Bargieri, Daniel Youssef
Lacerda, Marcus Vinicius Guimarães De
Lemos Cravo, Pedro Vitor
Sunnerhagen, Per
Prudêncio, Miguel
Andrade, Carolina Horta
Pinto Lopes, Stefanie Costa
Carazzolle, Marcelo Falsarella
Tilley, Leann
Bilsland, Elizabeth
Borges, Júlio César
Maranhão Costa, Fabio Trindade
author_role author
author2 Da Silva, Noeli Soares Melo
Spillman, Natalie
Kayano, Ana Carolina Andrade Vitor
Cassiano, Gustavo Capatti
Vasconcelos, Adrielle Ayumi
Camargo, Antônio Pedro
Da Silva, Djane Clarys Baia
Fontinha, Diana
Salazar Alvarez, Luis Carlos
Ferreira, Letícia Tiburcio
Peralis Tomaz, Kaira Cristina
Neves, Bruno Junior
Almeida, Ludimila Dias
Bargieri, Daniel Youssef
Lacerda, Marcus Vinicius Guimarães De
Lemos Cravo, Pedro Vitor
Sunnerhagen, Per
Prudêncio, Miguel
Andrade, Carolina Horta
Pinto Lopes, Stefanie Costa
Carazzolle, Marcelo Falsarella
Tilley, Leann
Bilsland, Elizabeth
Borges, Júlio César
Maranhão Costa, Fabio Trindade
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Vector borne diseases and pathogens (VBD)
Global Health and Tropical Medicine (GHTM)
Instituto de Higiene e Medicina Tropical (IHMT)
RUN
dc.contributor.author.fl_str_mv Tavella, Tatyana Almeida
Da Silva, Noeli Soares Melo
Spillman, Natalie
Kayano, Ana Carolina Andrade Vitor
Cassiano, Gustavo Capatti
Vasconcelos, Adrielle Ayumi
Camargo, Antônio Pedro
Da Silva, Djane Clarys Baia
Fontinha, Diana
Salazar Alvarez, Luis Carlos
Ferreira, Letícia Tiburcio
Peralis Tomaz, Kaira Cristina
Neves, Bruno Junior
Almeida, Ludimila Dias
Bargieri, Daniel Youssef
Lacerda, Marcus Vinicius Guimarães De
Lemos Cravo, Pedro Vitor
Sunnerhagen, Per
Prudêncio, Miguel
Andrade, Carolina Horta
Pinto Lopes, Stefanie Costa
Carazzolle, Marcelo Falsarella
Tilley, Leann
Bilsland, Elizabeth
Borges, Júlio César
Maranhão Costa, Fabio Trindade
dc.subject.por.fl_str_mv chaperone inhibitor
chemogenomics
malaria
proteostasis
violacein
Structural Biology
Infectious Diseases
SDG 1 - No Poverty
SDG 3 - Good Health and Well-being
SDG 9 - Industry, Innovation, and Infrastructure
topic chaperone inhibitor
chemogenomics
malaria
proteostasis
violacein
Structural Biology
Infectious Diseases
SDG 1 - No Poverty
SDG 3 - Good Health and Well-being
SDG 9 - Industry, Innovation, and Infrastructure
description Antimalarial drugs with novel modes of action and wide therapeutic potential are needed to pave the way for malaria eradication. Violacein is a natural compound known for its biological activity against cancer cells and several pathogens, including the malaria parasite, Plasmodium falciparum (Pf). Herein, using chemical genomic profiling (CGP), we found that violacein affects protein homeostasis. Mechanistically, violacein binds Pf chaperones, PfHsp90 and PfHsp70-1, compromising the latter's ATPase and chaperone activities. Additionally, violacein-treated parasites exhibited increased protein unfolding and proteasomal degradation. The uncoupling of the parasite stress response reflects the multistage growth inhibitory effect promoted by violacein. Despite evidence of proteotoxic stress, violacein did not inhibit global protein synthesis via UPR activation - a process that is highly dependent on chaperones, in agreement with the notion of a violacein-induced proteostasis collapse. Our data highlight the importance of a functioning chaperone-proteasome system for parasite development and differentiation. Thus, a violacein-like small molecule might provide a good scaffold for development of a novel probe for examining the molecular chaperone network and/or antiplasmodial drug design.
publishDate 2021
dc.date.none.fl_str_mv 2021-04-30T22:44:37Z
2021-03-10
2021-03-10T00:00:00Z
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.uri.fl_str_mv http://hdl.handle.net/10362/116523
url http://hdl.handle.net/10362/116523
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 2373-8227
PURE: 29207291
https://doi.org/10.1021/acsinfecdis.0c00454
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 8
application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv mluisa.alvim@gmail.com
_version_ 1817545794374336512