Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , |
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. |
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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 |
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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 |
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1817545794374336512 |