TY - JOUR
T1 - Identification of tyrosine kinase inhibitors that halt Plasmodium falciparum parasitemia
AU - Kesely, Kristina
AU - Noomuna, Panae
AU - Vieth, Michal
AU - Hipskind, Philip
AU - Haldar, Kasturi
AU - Pantaleo, Antonella
AU - Turrini, Francesco
AU - Low, Philip S.
N1 - Publisher Copyright:
Copyright: © 2020 Kesely et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
KW - Animals
KW - Antimalarials/therapeutic use
KW - Erythrocytes/drug effects
KW - Female
KW - Healthy Volunteers
KW - Humans
KW - Malaria/drug therapy
KW - Malaria, Falciparum/drug therapy
KW - Male
KW - Parasitemia/drug therapy
KW - Parasites/metabolism
KW - Peptide Library
KW - Phosphorylation
KW - Plasmodium falciparum/drug effects
KW - Protein Kinase Inhibitors/pharmacology
KW - Protein-Tyrosine Kinases/antagonists & inhibitors
KW - Syk Kinase/antagonists & inhibitors
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U2 - 10.1371/journal.pone.0242372
DO - 10.1371/journal.pone.0242372
M3 - Article
C2 - 33180822
AN - SCOPUS:85096060746
SN - 1932-6203
VL - 15
SP - e0242372
JO - PLoS ONE
JF - PLoS ONE
IS - 11
M1 - e0242372
ER -