Killing the hypnozoite--drug discovery approaches to prevent relapse in Plasmodium vivax

Abstract

The eradication of malaria will only be possible if effective, well-tolerated medicines kill hypnozoites in vivax and ovale malaria, and thus prevent relapses in patients. Despite progress in the 8-aminoquinoline series, with tafenoquine in Phase III showing clear benefits over primaquine, the drug discovery challenge to identify hypnozoiticidal or hypnozoite-activating compounds has been hampered by the dearth of biological tools and assays, which in turn has been limited by the immense scientific and logistical challenges associated with accessing relevant human tissue and sporozoites. This review summarises the existing drug discovery series and approaches concerning the goal to block relapse.

Keywords: Drug discovery assays; Hypnozoite,; Plasmodium vivax,; Radical cure,; Strategy,.

Figure 1

Liver stage life cycle of Plasmodium spp. A proportion of vivax sporozoites differentiate to a hypnozoite form that ultimately reactivates and proliferates leading to a blood-stage relapse.

Figure 2

Total dose of primaquine versus % cure.

Figure 3

The structures of leading 8-aminoquinolines: primaquine, tafenoquine.

Figure 4

Structures of NPC1161C and enantiomers B and C, and bulaquine.

Figure 5

Structures of quinolones, RC-12 and imidazolidinone – 8e.

Figure 6

Structures of KAI407 and optimised KDU691.

Figure 7

Phylogenetic tree of Plasmodium spp causing malaria in different species adapted from Hall. Branches are not to scale but represent how closely related each species is with each other. The shorter the branch, the closer the genome of each Plasmodium spp. Each plasmodia species is associated with its natural vertebrate host and the number of assembled whole-genome sequences that are publically available, either in public databases or through genome centres is also labelled as described by Hall.