TY - JOUR
T1 - Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
AU - Tavella, Tatyana Almeida
AU - Da Silva, Noeli Soares Melo
AU - Spillman, Natalie
AU - Kayano, Ana Carolina Andrade Vitor
AU - Cassiano, Gustavo Capatti
AU - Vasconcelos, Adrielle Ayumi
AU - Camargo, Antônio Pedro
AU - Da Silva, Djane Clarys Baia
AU - Fontinha, Diana
AU - Salazar Alvarez, Luis Carlos
AU - Ferreira, Letícia Tiburcio
AU - Peralis Tomaz, Kaira Cristina
AU - Neves, Bruno Junior
AU - Almeida, Ludimila Dias
AU - Bargieri, Daniel Youssef
AU - Lacerda, Marcus Vinicius Guimarães De
AU - Lemos Cravo, Pedro Vitor
AU - Sunnerhagen, Per
AU - Prudêncio, Miguel
AU - Andrade, Carolina Horta
AU - Pinto Lopes, Stefanie Costa
AU - Carazzolle, Marcelo Falsarella
AU - Tilley, Leann
AU - Bilsland, Elizabeth
AU - Borges, Júlio César
AU - Maranhão Costa, Fabio Trindade
PY - 2021/3/10
Y1 - 2021/3/10
N2 - 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.
AB - 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.
KW - chaperone inhibitor
KW - chemogenomics
KW - malaria
KW - proteostasis
KW - violacein
UR - http://www.scopus.com/inward/record.url?scp=85103495673&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.0c00454
DO - 10.1021/acsinfecdis.0c00454
M3 - Article
C2 - 33689276
AN - SCOPUS:85103495673
SN - 2373-8227
VL - 7
SP - 759
EP - 776
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 4
ER -
