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Diatretol, an α, α'-dioxo-diketopiperazine, is a potent in vitro and in vivo antimalarial.

ABSTRACT: A fungal metabolite, diatretol, has shown to be a promising antimalarial agent. Diatretol displayed potent in vitro antiparasitic activity against the Plasmodium falciparum K1 strain, with an IC₅₀ value of 378 ng ml^-1, as well as in vivo efficacy in a Plasmodium berghei-infected mice model, with ca. 50% inhibition at 30 mg/kg (p.o.).

SUBMITTER: Ishiyama A

PROVIDER: S-EPMC7807217 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Diatretol, an α, α'-dioxo-diketopiperazine, is a potent in vitro and in vivo antimalarial.

Ishiyama Aki A Hokari Rei R Nonaka Kenichi K Chiba Takuya T Miura Hiromi H Otoguro Kazuhiko K Iwatsuki Masato M

The Journal of antibiotics 20210114 4

A fungal metabolite, diatretol, has shown to be a promising antimalarial agent. Diatretol displayed potent in vitro antiparasitic activity against the Plasmodium falciparum K1 strain, with an IC<sub>50</sub> value of 378 ng ml<sup>-1</sup>, as well as in vivo efficacy in a Plasmodium berghei-infected mice model, with ca. 50% inhibition at 30 mg/kg (p.o.). ...[more]

PMID: 33446930

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Project description:BackgroundBy 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.ResultsAttempts 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.ConclusionsInhibiting 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.

Dataset Information

Diatretol, an α, α'-dioxo-diketopiperazine, is a potent in vitro and in vivo antimalarial.

Publications

Diatretol, an α, α'-dioxo-diketopiperazine, is a potent in vitro and in vivo antimalarial.

Similar Datasets

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