Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFG |
Texto Completo: | http://repositorio.bc.ufg.br/tede/handle/tede/11754 |
Resumo: | Paracoccidioidomycosis is one of the most important systemic mycoses in Latin America. The infection occurs through the inhalation of fungal propagules belonging to Paracoccidioides genus that are present in soils, being largely associated with the contamination of rural workers, who are constantly exposed to this potentially contaminated material. Even more than a century after its discovery, the treatment of this infection with the currently available antifungal arsenal still represents a challenge, due to the long treatment time required, as well as the high toxicity of the drugs used. These questions highlight the need for research to develop and characterize new compounds with the potential to inhibit the growth of these microorganisms. In this sense, a class of molecules called chalcones has shown great versatility for demonstrating broad biological properties, including antifungal activity among them. Through a virtual screening methodology, a chalcone derivative named compound 3 was identified by our group as a promising inhibitor of Paracoccidioides spp. Thus, in order to understand the mode of action of compound 3, we applied a proteomic approach to identify the induced and repressed proteins of P. brasiliensis in the presence of compound 3. In addition, validation assays were performed on the results found. The analysis indicated that the compound can cause an imbalance in the fungal energy homeostasis by reducing the activity of the glycolytic pathway, beta-oxidation and citric acid cycle. In vitro validations also demonstrated that reactive oxygen species accumulate within the cells during exposure to compound 3, which can destabilize cellular components such as the plasma membrane. The molecular docking assay between compound 3 and the enzyme dihydropteroate synthase, which had its expression induced after the treatment, suggest that compound 3 may act as an inhibitor of this protein, impairing the folate biosynthesis that participates as a cofactor in synthesis of nucleotides and some amino acids. Therefore, these data support the efficiency of compound 3 in producing imbalances in key pathways for the P. brasiliensis' metabolic maintenance, contributing to its antifungal role. |
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Pereira, Maristelahttp://lattes.cnpq.br/1345781867765758Silva, Kleber Santiago Freitas ehttp://lattes.cnpq.br/3813868830071259Pereira, MaristelaCurcio, Juliana Santana deSoares, Célia Maria de Almeidahttp://lattes.cnpq.br/1104307184099700Carvalho Júnior, Marcos Antonio Batista de2021-11-18T11:58:48Z2021-11-18T11:58:48Z2021-09-30CARVALHO JÚNIOR, M. A. B. Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona. 2021. 95 f. Dissertação (Mestrado em Genética e Biologia Molecular) - Universidade Federal de Goiás, Goiânia, 2021.http://repositorio.bc.ufg.br/tede/handle/tede/11754ark:/38995/0013000008znnParacoccidioidomycosis is one of the most important systemic mycoses in Latin America. The infection occurs through the inhalation of fungal propagules belonging to Paracoccidioides genus that are present in soils, being largely associated with the contamination of rural workers, who are constantly exposed to this potentially contaminated material. Even more than a century after its discovery, the treatment of this infection with the currently available antifungal arsenal still represents a challenge, due to the long treatment time required, as well as the high toxicity of the drugs used. These questions highlight the need for research to develop and characterize new compounds with the potential to inhibit the growth of these microorganisms. In this sense, a class of molecules called chalcones has shown great versatility for demonstrating broad biological properties, including antifungal activity among them. Through a virtual screening methodology, a chalcone derivative named compound 3 was identified by our group as a promising inhibitor of Paracoccidioides spp. Thus, in order to understand the mode of action of compound 3, we applied a proteomic approach to identify the induced and repressed proteins of P. brasiliensis in the presence of compound 3. In addition, validation assays were performed on the results found. The analysis indicated that the compound can cause an imbalance in the fungal energy homeostasis by reducing the activity of the glycolytic pathway, beta-oxidation and citric acid cycle. In vitro validations also demonstrated that reactive oxygen species accumulate within the cells during exposure to compound 3, which can destabilize cellular components such as the plasma membrane. The molecular docking assay between compound 3 and the enzyme dihydropteroate synthase, which had its expression induced after the treatment, suggest that compound 3 may act as an inhibitor of this protein, impairing the folate biosynthesis that participates as a cofactor in synthesis of nucleotides and some amino acids. Therefore, these data support the efficiency of compound 3 in producing imbalances in key pathways for the P. brasiliensis' metabolic maintenance, contributing to its antifungal role.A paracoccidioidomicose é uma das mais importantes micoses sistêmicas na América latina. Ela ocorre a partir da inalação de propágulos dos fungos do gênero Paracoccidioides presentes nos solos, estando geralmente associada à contaminação de trabalhadores rurais, os quais são constantemente expostos a manipulação deste material potencialmente contaminado. Mesmo mais de um século após o seu descobrimento, o tratamento dessa infecção com o arsenal antifúngico atualmente disponível ainda representa um desafio, devido ao longo tempo de tratamento necessário, bem como à alta toxicidade dos medicamentos utilizados. Essas questões evidenciam a necessidade de pesquisas de desenvolvimento e caracterização de novos compostos com potencial para inibir o crescimento desses microrganismos. Nesse sentido, uma classe de moléculas denominadas chalconas, tem apresentado grande versatilidade por demonstrarem amplas propriedades biológicas, incluindo entre elas a atividade antifúngica. Através de uma metodologia de triagem virtual, um derivado chalcona nomeado de composto 3 foi identificado pelo nosso grupo como uma promissora molécula inibidora de Paracoccidioides spp. Dessa forma, com o objetivo de compreender o modo de ação do composto 3, utilizamos uma abordagem proteômica afim de identificar as proteínas induzidas e reprimidas de P. brasiliensis na presença do composto 3. Em adição, foram realizados ensaios de validação dos resultados encontrados. As análises indicaram que o composto 3 pode provocar um desequilíbrio na homeostase energética do fungo pela redução da atividade da via glicolítica, da beta-oxidação e do ciclo do ácido cítrico. As validações in vitro também demonstraram que espécies reativas de oxigênio se acumulam dentro das células durante a exposição ao composto 3, o que pode desestabilizar componentes celulares como a membrana plasmática. Em última análise, o ensaio de ancoragem molecular entre o composto 3 e a enzima diidropteroato sintase, que teve sua expressão induzida após o tratamento, sugere que o composto 3 possa atuar como um inibidor dessa proteína, prejudicando a síntese de folato que participa como cofator na biossíntese de nucleotídeos e alguns aminoácidos. Portanto, os dados suportam a eficiência do composto 3 em produzir desequilíbrios em vias chave para a manutenção metabólica do organismo, contribuindo para o seu papel antifúngico.Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2021-11-17T16:15:19Z No. of bitstreams: 2 Dissertação - Marcos Antonio Batista de Carvalho Júnior - 2021.pdf: 2886739 bytes, checksum: 5cf3ba5acd32cdf4302025809981558b (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5)Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2021-11-18T11:58:48Z (GMT) No. of bitstreams: 2 Dissertação - Marcos Antonio Batista de Carvalho Júnior - 2021.pdf: 2886739 bytes, checksum: 5cf3ba5acd32cdf4302025809981558b (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5)Made available in DSpace on 2021-11-18T11:58:48Z (GMT). No. of bitstreams: 2 Dissertação - Marcos Antonio Batista de Carvalho Júnior - 2021.pdf: 2886739 bytes, checksum: 5cf3ba5acd32cdf4302025809981558b (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5) Previous issue date: 2021-09-30Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de GoiásPrograma de Pós-graduação em Genética e Biologia Molecular (ICB)UFGBrasilInstituto de Ciências Biológicas - ICB (RG)Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessChalconaAntifungoParacoccidioides brasiliensisProteômicaAncoragem molecularChalconeAntifungalParacoccidioides brasiliensisProteomicMolecular dockingCIENCIAS BIOLOGICAS::GENETICAIdentificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalconaProteomic identification of metabolic changes in Paracoccidioides brasiliensis induced by chalcone derivativeinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesis57500500500500231661reponame:Repositório Institucional da UFGinstname:Universidade Federal de Goiás (UFG)instacron:UFGORIGINALDissertação - Marcos Antonio Batista de Carvalho Júnior - 2021.pdfDissertação - Marcos Antonio Batista de Carvalho Júnior - 2021.pdfapplication/pdf2886739http://repositorio.bc.ufg.br/tede/bitstreams/1be16286-1bca-4f50-a5d7-271ee484abf4/download5cf3ba5acd32cdf4302025809981558bMD53LICENSElicense.txtlicense.txttext/plain; charset=utf-81748http://repositorio.bc.ufg.br/tede/bitstreams/4b89e508-dca4-4042-897b-5df3b17a78b4/download8a4605be74aa9ea9d79846c1fba20a33MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805http://repositorio.bc.ufg.br/tede/bitstreams/2553d8cc-1743-4beb-af66-1f35a8257960/download4460e5956bc1d1639be9ae6146a50347MD52tede/117542021-11-18 08:58:48.889http://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 Internationalopen.accessoai:repositorio.bc.ufg.br:tede/11754http://repositorio.bc.ufg.br/tedeRepositório InstitucionalPUBhttp://repositorio.bc.ufg.br/oai/requesttasesdissertacoes.bc@ufg.bropendoar:2021-11-18T11:58:48Repositório Institucional da UFG - Universidade Federal de Goiás (UFG)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 |
dc.title.pt_BR.fl_str_mv |
Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona |
dc.title.alternative.eng.fl_str_mv |
Proteomic identification of metabolic changes in Paracoccidioides brasiliensis induced by chalcone derivative |
title |
Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona |
spellingShingle |
Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona Carvalho Júnior, Marcos Antonio Batista de Chalcona Antifungo Paracoccidioides brasiliensis Proteômica Ancoragem molecular Chalcone Antifungal Paracoccidioides brasiliensis Proteomic Molecular docking CIENCIAS BIOLOGICAS::GENETICA |
title_short |
Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona |
title_full |
Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona |
title_fullStr |
Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona |
title_full_unstemmed |
Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona |
title_sort |
Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona |
author |
Carvalho Júnior, Marcos Antonio Batista de |
author_facet |
Carvalho Júnior, Marcos Antonio Batista de |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Pereira, Maristela |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/1345781867765758 |
dc.contributor.advisor-co1.fl_str_mv |
Silva, Kleber Santiago Freitas e |
dc.contributor.advisor-co1Lattes.fl_str_mv |
http://lattes.cnpq.br/3813868830071259 |
dc.contributor.referee1.fl_str_mv |
Pereira, Maristela |
dc.contributor.referee2.fl_str_mv |
Curcio, Juliana Santana de |
dc.contributor.referee3.fl_str_mv |
Soares, Célia Maria de Almeida |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/1104307184099700 |
dc.contributor.author.fl_str_mv |
Carvalho Júnior, Marcos Antonio Batista de |
contributor_str_mv |
Pereira, Maristela Silva, Kleber Santiago Freitas e Pereira, Maristela Curcio, Juliana Santana de Soares, Célia Maria de Almeida |
dc.subject.por.fl_str_mv |
Chalcona Antifungo Paracoccidioides brasiliensis Proteômica Ancoragem molecular |
topic |
Chalcona Antifungo Paracoccidioides brasiliensis Proteômica Ancoragem molecular Chalcone Antifungal Paracoccidioides brasiliensis Proteomic Molecular docking CIENCIAS BIOLOGICAS::GENETICA |
dc.subject.eng.fl_str_mv |
Chalcone Antifungal Paracoccidioides brasiliensis Proteomic Molecular docking |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::GENETICA |
description |
Paracoccidioidomycosis is one of the most important systemic mycoses in Latin America. The infection occurs through the inhalation of fungal propagules belonging to Paracoccidioides genus that are present in soils, being largely associated with the contamination of rural workers, who are constantly exposed to this potentially contaminated material. Even more than a century after its discovery, the treatment of this infection with the currently available antifungal arsenal still represents a challenge, due to the long treatment time required, as well as the high toxicity of the drugs used. These questions highlight the need for research to develop and characterize new compounds with the potential to inhibit the growth of these microorganisms. In this sense, a class of molecules called chalcones has shown great versatility for demonstrating broad biological properties, including antifungal activity among them. Through a virtual screening methodology, a chalcone derivative named compound 3 was identified by our group as a promising inhibitor of Paracoccidioides spp. Thus, in order to understand the mode of action of compound 3, we applied a proteomic approach to identify the induced and repressed proteins of P. brasiliensis in the presence of compound 3. In addition, validation assays were performed on the results found. The analysis indicated that the compound can cause an imbalance in the fungal energy homeostasis by reducing the activity of the glycolytic pathway, beta-oxidation and citric acid cycle. In vitro validations also demonstrated that reactive oxygen species accumulate within the cells during exposure to compound 3, which can destabilize cellular components such as the plasma membrane. The molecular docking assay between compound 3 and the enzyme dihydropteroate synthase, which had its expression induced after the treatment, suggest that compound 3 may act as an inhibitor of this protein, impairing the folate biosynthesis that participates as a cofactor in synthesis of nucleotides and some amino acids. Therefore, these data support the efficiency of compound 3 in producing imbalances in key pathways for the P. brasiliensis' metabolic maintenance, contributing to its antifungal role. |
publishDate |
2021 |
dc.date.accessioned.fl_str_mv |
2021-11-18T11:58:48Z |
dc.date.available.fl_str_mv |
2021-11-18T11:58:48Z |
dc.date.issued.fl_str_mv |
2021-09-30 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
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masterThesis |
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dc.identifier.citation.fl_str_mv |
CARVALHO JÚNIOR, M. A. B. Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona. 2021. 95 f. Dissertação (Mestrado em Genética e Biologia Molecular) - Universidade Federal de Goiás, Goiânia, 2021. |
dc.identifier.uri.fl_str_mv |
http://repositorio.bc.ufg.br/tede/handle/tede/11754 |
dc.identifier.dark.fl_str_mv |
ark:/38995/0013000008znn |
identifier_str_mv |
CARVALHO JÚNIOR, M. A. B. Identificação proteômica de alterações metabólicas em Paracoccidioides brasiliensis induzidas por derivado de chalcona. 2021. 95 f. Dissertação (Mestrado em Genética e Biologia Molecular) - Universidade Federal de Goiás, Goiânia, 2021. ark:/38995/0013000008znn |
url |
http://repositorio.bc.ufg.br/tede/handle/tede/11754 |
dc.language.iso.fl_str_mv |
por |
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por |
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166 |
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1 |
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Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
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Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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Universidade Federal de Goiás |
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Programa de Pós-graduação em Genética e Biologia Molecular (ICB) |
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UFG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Instituto de Ciências Biológicas - ICB (RG) |
publisher.none.fl_str_mv |
Universidade Federal de Goiás |
dc.source.none.fl_str_mv |
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