Merck and the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, have confirmed their findings of a novel class of candidate antimalarial agents that blocks the multiple stages of the malaria parasite’s lifecycle that causes the disease.
New anti-malarial treatments are being developed by the researchers that will kill the parasite once it’s present inside the human body.
Novel dual inhibitors of plasmepsins IX and X (PMIX and PMX), have been identified by the researchers. The two proteases are essential to Plasmodium falciparum, the major cause of the most severe form of the disease.
Successive broods of malaria-causing parasites grow inside erythrocytes i.e. the red blood cells and destroy them and release daughter parasites called merozoites. These then continue the cycle by invading other erythrocytes.
The inhibitors are targets in anti-malarial drug discovery as they are involved in the process in which the malarial parasite enters erythrocytes and also in egress of the parasite from cells.
This process and maturation of certain protein required for replication can be blocked when PMIX and PMX are inhibited. The proper functioning of PMX is also needed within merozoites to enter new erythrocytes.
The preclinical research conducted by the scientists revealed that screening a targeted library of protease inhibitors can kill the P. falciparum parasite.
Moreover, to determine in vivo activity against P. berghei infection (a parasite that causes malaria in rodents), the two most potent in inhibiting the replication of P. falciparum in vitro were administered to mice. Although, no desirable pharmacokinetic attributes was obtained from the compounds, they however suppressed P. berghei parasitemia.
To identify compounds with required drug-like properties, optimization studies were conducted by the researchers, resulting in the identification of WM382, a compound that acts as a dual inhibitor of PMIX and PMX and restrains the growth of P. falciparum and P. knowlesi, a parasite that causes malaria in humans and other primates.
Study revealed that the mice of P. berghei was cured with the oral administration of WM382 and also prevented blood infection from the liver. Besides, it was also effective against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes.
The efficiency of WM382 to block transmission is an important attribute for an antimalarial drug as this characteristic could reduce both the incidence and spread of malaria.
A drug regimen that could act on novel targets at multiple stages of the malaria parasite’s lifecycle would not increase the utility of the regimen, but may potentially help eradicate a major cause of malaria in the future.