Characterization of the activity of the protein aggregation inhibitor YAT2150 as a new antimalarial mechanism

The current arsenal of malaria drugs is insufficient to make progress toward eradicating the disease, a situation that is worsened by the rampant evolution of resistance in Plasmodium. This situation demands immediate efforts to discover new compounds that are easily and affordably obtained, ideally belonging to chemical classes where other antimalarials have not been described, with several molecular targets in the pathogen, and whose mechanism of action is different from that of drugs currently in use.

Although potentially toxic protein aggregates are abundant in all phases of the malaria parasite, the results of the current national plan draft indicate that protein aggregation-stimulating peptides in Plasmodium falciparum do not affect its viability. However, in the same project, evidence was obtained showing that certain protein aggregation inhibitor compounds are lethal to the pathogen at concentrations in the low nM range. One of these compounds, the styrylpyridinium salt YAT2150—the active component of a commercial product used to stain protein deposits in living cells—is particularly attractive due to its rapid, simple, and inexpensive synthesis and its activity against blood stages of P. falciparum with an in vitro IC₅₀ of 90 nM.

This compound, a potent inhibitor of amyloid beta 1–40 peptide aggregation, has no adverse effects in mice below 10 mg/kg and, since it emits fluorescence upon contact with Plasmodium, it serves as a theranostic agent.

The results of this study will inform the physiological role of protein aggregation in the malaria parasite. Since dysregulating proteostasis potentially affects multiple gene products, rapid resistance evolution is not expected. In addition, YAT2150 belongs to a chemical class with no previously described antimalarials, so Plasmodium will not be able to adapt existing resistance mechanisms to similar compounds.

The results of the characterization of the in vitro activity of the drug encapsulated in immunoliposomes, the study of its antimalarial mechanism, and the determination of its in vivo activity and the probability of resistance evolution will be decisive in determining whether YAT2150 is a candidate for clinical trials leading to its development as a new medicine against malaria.

Considering the economic context of this disease, several properties of YAT2150—high activity against blood stages of the parasite, low in vivo toxicity, belonging to a new family of antimalarials, affordable synthesis, and long-term stability at room temperature—present it as a potentially key player in future efforts leading to the eradication of malaria.

Project details

Basic Science
Drug Resistance
Drug-based Strategies
Enabling Technologies & Assays

Jan 2021

$214,624

Spain