Repurposing Drugs to Fight Hepatic Malaria Parasites

Abstract

Malaria remains one of the most prevalent infectious diseases worldwide, primarily affecting some of the most vulnerable populations around the globe. Despite achievements in the treatment of this devastating disease, there is still an urgent need for the discovery of new drugs that tackle infection by Plasmodium parasites. However, de novo drug development is a costly and time-consuming process. An alternative strategy is to evaluate the anti-plasmodial activity of compounds that are already approved for other purposes, an approach known as drug repurposing. Here, we will review efforts to assess the anti-plasmodial activity of existing drugs, with an emphasis on the obligatory and clinically silent liver stage of infection. We will also review the current knowledge on the classes of compounds that might be therapeutically relevant against Plasmodium in the context of other communicable diseases that are prevalent in regions where malaria is endemic. Repositioning existing compounds may constitute a faster solution to the current gap of prophylactic and therapeutic drugs that act on Plasmodium parasites, overall contributing to the global effort of malaria eradication.

Structural insights into Plasmodium PPIases

“…The question remains as to the function of other PPIases and why the parasite needs multiple PPIases. The possible role of these PPIases in liver stage (Derbyshire et al, 2012;Fontinha et al, 2020) can be explored, though most of them are abundantly produced in the intraerythrocytic stage. Their inhibitors also act on stages which correlate with this (Supplementary Figure 1).…”

Studies of Potency and Efficacy of an Optimized Artemisinin-Quinoline Hybrid against Multiple Stages of the Plasmodium Life Cycle

“…In addition to its activity against the parasite's asexual blood stages, it is desirable for a novel antimalarial agent to also demonstrate activity against the hepatic stage of infection, which is obligatory for the onset of blood infection and, depending on the parasite species, can be involved in disease relapses (as is the case of P. vivax infection) [30,31]. Additionally, activity against the sexual blood stages of Plasmodium is desirable for a novel antimalarial, as these stages are involved in parasite transmission to the invertebrate host [32,33].…”

4,9‐Diaminoacridines and 4‐Aminoacridines as Dual‐Stage Antiplasmodial Hits

“…In the pursuit of such efforts, one must bear in mind that only cost‐effective approaches towards affordable medicines will have a real impact in the fight against malaria, which mainly affects low to middle income countries. Thus, priority should be given to the repurposing of existing drugs for malaria, [6] or to the rescuing of antimalarial pharmacophores towards the development of new multi‐target compounds [7] …”

“…[5] In the pursuit of such efforts, one must bear in mind that only cost-effective approaches towards affordable medicines will have a real impact in the fight against malaria, which mainly affects low to middle income countries. Thus, priority should be given to the repurposing of existing drugs for malaria, [6] or to the rescuing of antimalarial pharmacophores towards the development of new multi-target compounds. [7] Quinacrine (QN, Figure 1) was the first clinically tested synthetic antimalarial drug; [8] it is a potent blood schizonticide, but its serious adverse effects led to its rapid replacement by chloroquine (CQ, Figure 1), whose efficiency, oral bioavailability, and safety were far superior to those of QN.…”