Description
By 2016 the emergence of artemisinin and partner drug resistance in Plasmodium falciparum was detected in the Greater Mekong Subregion, and 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 drugs with little-exploited targets in the malaria parasite.
We have recently characterized YAT2150, a first-in-class, fast-acting antiplasmodial drug with an in vitro half maximal inhibitory concentration (IC50) of ca. 90 nM against P. falciparum blood stages, gametocytes, and chloroquine- and artemisinin-resistant strains. YAT2150 has an inexpensive, easy and rapid synthesis (only two steps), and a long shelf life (months) at room temperature. It strongly fluoresces when in contact with the pathogen inside red blood cells, and has the capacity of strongly labelling P. falciparum ring stages in clinical samples. YAT2150 reduces the aggregation of the parasite’s proteome according to thioflavin T assays. Unlike most other current antimalarial drugs which target products of one or a few genes, YAT2150’s presumed mode of action (inhibition of protein aggregation in the parasite) will likely target multiple proteins, hampering a rapid resistance evolution by the pathogen. Moreover, YAT2150 belongs to a novel chemical family where no other antimalarial has been described to date. These properties suggested that resistance against this drug would not appear easily.
We have performed assays to select P. falciparum parasites resistant to YAT2150 concentrations ranging from 3× to ¼ the in vitro IC50 of the compound and performed a cross-resistance assessment in P. falciparum lines harboring mutations that make them resistant to a variety of antimalarial drugs. Resistant parasites to YAT2150 did not emerge in vitro after 60 days of incubation. Transcriptomic (RNAseq) and proteomic (Cellular Thermal Shift Assay) analyses identified several significantly up- and down-regulated transcripts and stabilized/destabilized proteins upon YAT2150 treatment of P. falciparum cultures. Although no particular drug targets could be singled out, several of the identified proteins have been found to be involved in key cellular processes like, among others, carbohydrate metabolism, parasite invasion, and mitochondrial transport.
The results presented herein support an antiplasmodial mechanism based on the disruption of several molecular targets, perhaps by interfering with the formation of liquid-liquid phase separation biomolecular condensates by transcription factors that are essential for responses to stresses that are known to affect protein aggregation and to which the parasite is exposed (e.g., changes in temperature, pH or redox potential, and certain drugs). Our results postulate YAT2150 as an ‘irresistible’ antimalarial drug deserving attention in a likely future scenario of widespread resistance to current front-line antimalarial treatments.
Funding: This work was supported by grants PID2021-128325OB-I00 and PDC2022-133085-I00 (XF-B), and PID2020-118127RB-I00 (DM-T), funded by Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación (MCIN/AEI/10.13039/501100011033), Spain, which included FEDER funds. We acknowledge support from MCIN/AEI through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S). This research is part of the Barcelona Institute for Global Health's Program on the Molecular Mechanisms of Malaria which is partially supported by the Fundación Ramón Areces.
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