A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.
Maher SP., Bakowski MA., Vantaux A., Flannery EL., Andolina C., Gupta M., Antonova-Koch Y., Argomaniz M., Cabrera-Mora M., Campo B., Chao AT., Chatterjee AK., Cheng WT., Cooper CA., Cottier K., Galinski MR., Harupa-Chung A., Ji H., Joseph SB., Lenz T., Lonardi S., Matheson J., Mikolajczak SA., Padín-Irizarry V., Pan K., Péneau J., Prudhomme J., Roesch C., Sabnis SS., Saney CL., Sattabongkot J., Sereshki S., Suriyakan S., Moeller T., Ubalee R., Wang Y., Wasisakun P., Yin J., McNamara CW., Joyner CJ., Nosten F., Witkowski B., Le Roch KG., Kyle DE.
UNLABELLED: Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets, we screened the Repurposing, Focused Rescue, and Accelerated Medchem library against P. vivax liver stages and identified the DNA methyltransferase inhibitors hydralazine and cadralazine as active against hypnozoites. We then used bisulfite sequencing and immunostaining to identify cytosine modifications in the infectious stage (sporozoites) and liver stages, respectively. A subsequent screen of epigenetic inhibitors revealed hypnozoites are broadly sensitive to histone acetyltransferase and methyltransferase inhibitors, indicating that several epigenetic mechanisms are likely modulating hypnozoite persistence. Our data present an avenue for the discovery and development of improved radical cure antimalarials. ONE-SENTENCE SUMMARY: A drug repurposing screen reveals antihypertension drugs are active against P. vivax hypnozoites and epigenetic mechanisms play a role in hypnozoite quiescence.