"Completely different" designer molecule could keep us one step ahead of drug-resistant malaria
The fight against malaria is enough of a struggle as it is. Making things worse, however, is the ability of the parasites behind it to develop resistance to our very best drugs, a pattern that has repeatedly played out over decades. Scientists have designed a new molecule they say could keep us ahead of the game, taking the best parts of a human protein to form a potent weapon that takes out the parasite before it gets any bright ideas.
Malaria kills a person every 90 seconds, such is its prevalence. The diseases arises from the parasite Plasmodium and its variants, and although drugs do exist to treat it, hundreds of thousands of people succumb to the mosquito-borne disease every year, with hundreds of millions more infected.
But scientists fear that today's most effective anti-malaria drugs may be rendered ineffective tomorrow due to the rise of drug-resistant bacteria, a threat that looms over the entire medical spectrum. Among those scientists is Australia National University's Brendan McMorran, who leads a research group dedicated to genetics and infectious diseases.
"Most recently, in the past decade, resistance to the best current drug called artemesinin has developed," McMorran tells New Atlas. "Currently we know that artemisinin resistance has spread throughout the southeast Asian countries bordering the greater Mekong river basin, but there is a high risk it will continue to spread to neighboring regions, and even to Africa, where it would cause a global health catastrophe.
"We are currently one step ahead with our antimalarial drugs, but the dire history of antimalarial drug resistance tells us that it is only a matter of time until this becomes more widespread."
McMorran led a team of researchers in developing a new designer molecule they hope can put the brakes on this evolution of drug resistance. Its basis is the human protein platelet factor 4 (PF4), which has some useful properties, namely that it is the only human protein known to kill malarial parasites.
But it also triggers an immune response that can worsen symptoms, and itself is too large to serve as a good candidate for developing into a drug. So McMorran and his team got to work on copying the critical parts of the protein and packing them into a smaller molecule, or peptide.
"We copied a region of the PF4 protein from human platelets that looked a lot like defence peptides from other organisms," McMorran explains. "The shape and composition of this region allows it to recognize infected red blood cells, but most importantly to destroy internal malaria parasite membranes."
The researchers put the molecule up against malarial parasites cultured in human red cells in the lab. They observed the peptide selectively penetrate the parasites and disrupt their digestive vacuole, killing them off while leaving the host cell unharmed. According to the team, this is "completely different" to how current antimalarial drugs work, and finding new ways to kill the parasite is fundamental to the development of next-generation drugs.
"Peptide drugs have a larger target than conventional antimalarial drugs, which is very important in countering the development of drug resistance," says McMorran. "Our lead peptides kill parasites through their exquisite ability to distinguish between infected red blood cells and healthy cells, and their ability to enter inside infected cells to destroy parasite membranes, without damaging the host cell membranes."
While the researchers are excited about the first iteration of their molecule, they acknowledge that a lot of work is to be done before they can start testing it on humans.
"Before human trials become an option, we will first improve the potency of our lead molecules by adapting them to achieve dual targeting of parasite membranes and key intracellular parasite enzymes," says McMorran. "These leads will be tested for their safety and ability to kill parasites in mice. Following these studies, we will have a better understanding of how to translate our peptide drug leads for testing in humans."
The research was published in the journal Cell Chemical Biology.
Source: Australian National University