Author(s):
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
Date: 2021
Persistent ID: http://hdl.handle.net/10362/116523
Origin: Repositório Institucional da UNL
Subject(s): 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.
