Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
| Autor: | Fabio T. M. Costa, Júlio César Borges, Elizabeth Bilsland, Antonio P. Camargo, Carolina Horta Andrade, Diana Fontinha, Letícia Tiburcio Ferreira, Natalie J. Spillman, Miguel Prudêncio, Per Sunnerhagen, Djane Clarys Baia da Silva, Stefanie C. P. Lopes, Ana Carolina A. V. Kayano, Pedro Cravo, Bruno J. Neves, Marcelo Falsarella Carazzolle, Ludimila Dias Almeida, Kaira C. P. Tomaz, Luis Carlos Salazar Alvarez, Marcus V. G. Lacerda, Leann Tilley, Adrielle Ayumi de Vasconcelos, Daniel Y. Bargieri, Noeli Soares Melo da Silva, Tatyana Almeida Tavella, Gustavo Capatti Cassiano |
|---|---|
| Přispěvatelé: | Vector borne diseases and pathogens (VBD), Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT) |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Indoles Plasmodium falciparum 030106 microbiology malaria Article Antimalarials violacein PLASMODIUM FALCIPARUM 03 medical and health sciences SDG 3 - Good Health and Well-being Structural Biology Heat shock protein proteostasis biology Chemistry Biological activity biology.organism_classification Small molecule Cell biology chaperone inhibitor 030104 developmental biology Infectious Diseases Proteostasis Chaperone (protein) SDG 1 - No Poverty Cancer cell chemogenomics biology.protein Unfolded protein response SDG 9 - Industry Innovation and Infrastructure Molecular Chaperones |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP ACS Infectious Diseases |
| ISSN: | 2373-8227 |
| Popis: | 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. publishersversion published |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|