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The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures

Authors :
Inés Bouzón-Arnáiz
Yunuen Avalos-Padilla
Arnau Biosca
Omar Caño-Prades
Lucía Román-Álamo
Javier Valle
David Andreu
Diana Moita
Miguel Prudêncio
Elsa M. Arce
Diego Muñoz-Torrero
Xavier Fernàndez-Busquets
Source :
BMC Biology, Vol 20, Iss 1, Pp 1-27 (2022)
Publication Year :
2022
Publisher :
BMC, 2022.

Abstract

Abstract Background By 2016, signs of emergence of Plasmodium falciparum resistance to artemisinin and partner drugs were detected in the Greater Mekong Subregion. Recently, the independent evolution of artemisinin resistance has also been reported in Africa and South America. This alarming scenario calls for the urgent development of new antimalarials with novel modes of action. We investigated the interference with protein aggregation, which is potentially toxic for the cell and occurs abundantly in all Plasmodium stages, as a hitherto unexplored drug target in the pathogen. Results Attempts to exacerbate the P. falciparum proteome’s propensity to aggregation by delivering endogenous aggregative peptides to in vitro cultures of this parasite did not significantly affect their growth. In contrast, protein aggregation inhibitors clearly reduced the pathogen’s viability. One such compound, the bis(styrylpyridinium) salt YAT2150, exhibited potent antiplasmodial activity with an in vitro IC50 of 90 nM for chloroquine- and artemisinin-resistant lines, arresting asexual blood parasites at the trophozoite stage, as well as interfering with the development of both sexual and hepatic forms of Plasmodium. At its IC50, this compound is a powerful inhibitor of the aggregation of the model amyloid β peptide fragment 1-40, and it reduces the amount of aggregated proteins in P. falciparum cultures, suggesting that the underlying antimalarial mechanism consists in a generalized impairment of proteostasis in the pathogen. YAT2150 has an easy, rapid, and inexpensive synthesis, and because it fluoresces when it accumulates in its main localization in the Plasmodium cytosol, it is a theranostic agent. Conclusions Inhibiting protein aggregation in Plasmodium significantly reduces the parasite’s viability in vitro. Since YAT2150 belongs to a novel structural class of antiplasmodials with a mode of action that potentially targets multiple gene products, rapid evolution of resistance to this drug is unlikely to occur, making it a promising compound for the post-artemisinin era.

Details

Language :
English
ISSN :
17417007
Volume :
20
Issue :
1
Database :
Directory of Open Access Journals
Journal :
BMC Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.24af2b626fe4416ac7f5ca762819cd1
Document Type :
article
Full Text :
https://doi.org/10.1186/s12915-022-01374-4