A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites

Quiescent liver stage Plasmodium vivax (hypnozoites) presents an overwhelming obstacle to treating malaria in vulnerable populations. Hydrazinophthalazines, a class of antihypertensive agents, have been implicated in direct inhibition of DNA methyltransferases and active against hypnozoites. We used bisulfite sequencing to evaluate the presence of the cytosine modification 5-methylcytosine (5mC) at single nucleotide resolution in the infectious stage (sporozoites) of P. vivax and P. cynomolgi. Although the presence and strand specificity of 5mC within exons and promoter regions will need to be directly linked to hypnozoite formation using single-cell techniques, this data presents an opportunity for further investigation into the viability of using DNMT inhibitors to treat persistent dormant liver-stage malaria.