Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity.

Autor: Tavella TA; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacinto da Silva, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil., da Silva NSM; Biochemistry and Biophysics of Proteins Group-São Carlos Institute of Chemistry-IQSC, University of São Paulo, Trabalhador Sancarlense Avenue, 400, BQ1, S27, São Carlos, SP 13566-590, Brazil., Spillman N; Department of Biochemistry, Bio 21 Institute, University of Melbourne, 30 Flemington Rd, Parkville, Melbourne,VIC 3052, Australia., Kayano ACAV; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacinto da Silva, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil., Cassiano GC; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacinto da Silva, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil.; Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, 1099-085 Lisboa, Portugal., Vasconcelos AA; Laboratory of Genomics and BioEnergy, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil., Camargo AP; Laboratory of Genomics and BioEnergy, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil., da Silva DCB; Leônidas & Maria Deane Institute, Fundação Oswaldo Cruz-FIOCRUZ, Manaus , AM 69057070, Brazil.; Fundação de Medicina Tropical-Dr. Heitor Vieira Dourado, Manaus, AM 69040-000, Brazil., Fontinha D; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-004 Lisboa, Portugal., Salazar Alvarez LC; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacinto da Silva, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil., Ferreira LT; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacinto da Silva, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil., Peralis Tomaz KC; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacinto da Silva, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil., Neves BJ; Laboratory of Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO 74605-170, Brazil.; LabChem-Laboratory of Cheminformatics, Centro Universitário de Anápolis-UniEVANGÉLICA, Anápolis, GO 75083-515, Brazil., Almeida LD; Synthetic Biology Laboratory, Department of Structural and Functional Biology, Institute of Biology, UNICAMP, Campinas, SP Brazil., Bargieri DY; Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Cidade Universitária 'Armando Salles Oliveira', São Paulo 05508-000, Brazil., Lacerda MVG; Fundação de Medicina Tropical-Dr. Heitor Vieira Dourado, Manaus, AM 69040-000, Brazil., Lemos Cravo PV; LabChem-Laboratory of Cheminformatics, Centro Universitário de Anápolis-UniEVANGÉLICA, Anápolis, GO 75083-515, Brazil.; Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, 1099-085 Lisboa, Portugal., Sunnerhagen P; Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Gothenburg, Sweden., Prudêncio M; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-004 Lisboa, Portugal., Andrade CH; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacinto da Silva, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil.; Laboratory of Molecular Modeling and Drug Design, LabMol, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO 74605-170, Brazil., Pinto Lopes SC; Leônidas & Maria Deane Institute, Fundação Oswaldo Cruz-FIOCRUZ, Manaus , AM 69057070, Brazil.; Fundação de Medicina Tropical-Dr. Heitor Vieira Dourado, Manaus, AM 69040-000, Brazil., Carazzolle MF; Laboratory of Genomics and BioEnergy, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil., Tilley L; Department of Biochemistry, Bio 21 Institute, University of Melbourne, 30 Flemington Rd, Parkville, Melbourne,VIC 3052, Australia., Bilsland E; Synthetic Biology Laboratory, Department of Structural and Functional Biology, Institute of Biology, UNICAMP, Campinas, SP Brazil., Borges JC; Biochemistry and Biophysics of Proteins Group-São Carlos Institute of Chemistry-IQSC, University of São Paulo, Trabalhador Sancarlense Avenue, 400, BQ1, S27, São Carlos, SP 13566-590, Brazil., Maranhão-Costa FTM; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacinto da Silva, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil.
Jazyk: angličtina
Zdroj: ACS infectious diseases [ACS Infect Dis] 2021 Apr 09; Vol. 7 (4), pp. 759-776. Date of Electronic Publication: 2021 Mar 10.
DOI: 10.1021/acsinfecdis.0c00454
Abstrakt: 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, Pf Hsp90 and Pf Hsp70-1, 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.
Databáze: MEDLINE