Tafenoquine: A Step toward Malaria Elimination

Abstract

There is a pressing need for compounds with broad-spectrum activity against malaria parasites at various life cycle stages to achieve malaria elimination. However, this goal cannot be accomplished without targeting the tenacious dormant liver-stage hypnozoite that causes multiple relapses after the first episode of illness. In the search for the magic bullet to radically cure Plasmodium vivax malaria, tafenoquine outperformed other candidate drugs and was approved by the U.S. Food and Drug Administration in 2018. Tafenoquine is an 8-aminoquinoline that inhibits multiple life stages of various Plasmodium species. Additionally, its much longer half-life allows for single-dose treatment, which will improve the compliance rate. Despite its approval and the long-time use of other 8-aminoquinolines, the mechanisms behind tafenoquine’s activity and adverse effects are still largely unknown. In this Perspective, we discuss the plausible underlying mechanisms of tafenoquine’s antiparasitic activity and highlight its role as a cellular stressor. We also discuss potential drug combinations and the development of next-generation 8-aminoquinolines to further improve the therapeutic index of tafenoquine for malaria treatment and prevention.

Chemoproteomics for Plasmodium Parasite Drug Target Discovery

“…Additionally, while sexual P. falciparum gametocytes can be produced in culture, low differentiation rates limit the amount of protein that can be obtained [7,90] . Perhaps the most challenging stage in the parasite's life cycle to interrogate with proteomics is the dormant P. vivax liver stage, termed hypnozoites, that causes relapsing malaria [91] . Despite these constraints, generating sufficient material for chemoproteomic studies may still be viable by establishing methods that enrich the specific life stages (gametocytes, liver‐stage schizonts, and liver‐stage hypnozoites) [90,92] .…”

Transmission blocking activity of low dose tafenoquine in healthy volunteers experimentally infected with Plasmodium falciparum

“…The major advantage of tafenoquine over primaquine is its considerably longer plasma elimination half-life (approximately 15 days) (12, 13) which allows for single dose (radical cure) or weekly administration for prophylaxis, thus reducing adherence issues commonly associated with primaquine dosing regimens (14). Although not currently approved for transmission blocking, the potential utility of tafenoquine for such is evident given its gametocytocidal activity in vitro (15) and transmission blocking activity in murine models (16). Like primaquine, tafenoquine can cause severe hemolytic anemia in G6PD-deficient individuals at currently recommended doses (17); however, as with primaquine, it is possible that a sufficient safety margin may be present for its therapeutic use in G6PD-deficient individuals (18).…”

Safety and Efficacy of Tafenoquine for Plasmodium vivax Malaria Prophylaxis and Radical Cure: Overview and Perspectives

“…Tafenoquine (TQ) is an antimalarial drug of the 8-aminoquinoline (8-AQ) class. 1 , 2 A single oral dose is more often than not effective for the radical cure of Plasmodium vivax malaria. TQ is thought to prevent malarial recurrence by killing a dormant plasmodial stage in the liver, for which I coined the term “hypnozoite” more than four decades ago.…”