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. 2020 Nov 12;15(11):e0242372.
doi: 10.1371/journal.pone.0242372. eCollection 2020.

Identification of tyrosine kinase inhibitors that halt Plasmodium falciparum parasitemia

Kristina Kesely  1   2 , Panae Noomuna  1   2 , Michal Vieth  3 , Philip Hipskind  4   5 , Kasturi Haldar  6 , Antonella Pantaleo  7 , Francesco Turrini  8 , Philip S Low  1   2
Affiliations

Identification of tyrosine kinase inhibitors that halt Plasmodium falciparum parasitemia

Kristina Kesely et al. PLoS One. .

Abstract

Although current malaria therapies inhibit pathways encoded in the parasite's genome, we have looked for anti-malaria drugs that can target an erythrocyte component because development of drug resistance might be suppressed if the parasite cannot mutate the drug's target. In search for such erythrocyte targets, we noted that human erythrocytes express tyrosine kinases, whereas the Plasmodium falciparum genome encodes no obvious tyrosine kinases. We therefore screened a library of tyrosine kinase inhibitors from Eli Lilly and Co. in a search for inhibitors with possible antimalarial activity. We report that although most tyrosine kinase inhibitors exerted no effect on parasite survival, a subset of tyrosine kinase inhibitors displayed potent anti-malarial activity. Moreover, all inhibitors found to block tyrosine phosphorylation of band 3 specifically suppressed P. falciparum survival at the parasite egress stage of its intra-erythrocyte life cycle. Conversely, tyrosine kinase inhibitors that failed to block band 3 tyrosine phosphorylation but still terminated the parasitemia were observed to halt parasite proliferation at other stages of the parasite's life cycle. Taken together these results suggest that certain erythrocyte tyrosine kinases may be important to P. falciparum maturation and that inhibitors that block these kinases may contribute to novel therapies for P. falciparum malaria.

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Conflict of interest statement

Authors PH and MV are employed by Eli Lilly and Company, but this does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Figures

Fig 1
Fig 1. Percent parasitemia of P. falciparum infected RBCs as a function of time following treatment with de-identified tyrosine kinase inhibitors at 1μM and 10μM concentrations.
The drugs were encoded based on their locations in 96-well plates as explained in the Methods section. Cultures were synchronized as described in Methods and kinase inhibitors were added ~16 hours after RBC invasion. The drug treatments were conducted in duplicate.
Fig 2
Fig 2. Percent inhibition of malaria parasitemia in RBCs following treatment with the most potent Eli Lilly compounds administered at 10 μM (panel A) and 1 μM (panel B) concentrations.
The indicated per cent inhibition was determined at the 22 hours post invasion time point in the parasite’s second life cycle (at the 70 hour time point in Fig 1), when control cultures were at the mature ring stage of development. All the treatments were done in duplicate.
Fig 3
Fig 3. Images of blood smears of parasite cultures obtained 66 hours post invasion.
Top left: Untreated (DMSO control) showing infected RBCs have progressed to the ring stage of their second life cycle after successful egress at the end of their first life cycle). Bottom left: Positive control of parasites treated with the well-known Syk inhibitor II showing stalled egress at the end of the first life cycle. Panels 1, 2, 3 and 4: Blood smears displaying the stages at which the de-identified drug terminated parasite maturation. Inhibitors 47F and 23D halted parasite maturation at ring stage, while 32C and 32D appear to halt the parasite at the trophozoite stage. Inhibitors 23B3 and 32A3 interrupted parasite development at the schizont stage. Syk phenotype inhibitors; 32E, 47H, 47A3 and 26D appear to stop the parasite from egressing at the segmenter stage as evidenced by the separated merozoites within infected cells.
Fig 4
Fig 4. Western blots displaying band 3 tyrosine phosphorylation and its inhibition by the Eli Lilly compounds found to display the Syk inhibitor phenotype.
All the selected inhibitors reduced parasite-induced band 3 tyrosine phosphorylation compared to controls (panel A). The compounds also inhibited diamide (top) and orthovanadate (bottom)-induced band 3 tyrosine phosphorylation, albeit with different potencies (panel B). It is worth noting that the inhibitors blocked diamide and orthovanadate-induced band 3 tyrosine with identical trends.
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