Violacein-induced chaperone system collapse underlies multistage antiplasmodial activity
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2021
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Resumo
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 activationa 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.
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Malaria, Chaperone inhibitor, Chemogenomics, Violacein, Proteostasis
Citação
TAVELLA, Tatyana Almeida et al. Violacein-induced chaperone system collapse underlies multistage antiplasmodial activity. ACS Infectious Diseases, Washington, v. 7, n. 4, p. 759-776, 2021. DOI: 10.1021/acsinfecdis.0c00454. Disponível em: https://pubs.acs.org/doi/full/10.1021/acsinfecdis.0c00454. Acesso em: 5 set. 2024.