Achilles was the mighty poster warrior of Homer’s Trojan War. When he was a baby, Achilles’ mother dunked him in the sacred River Styx to make his body weapon-proof, from head to toe. But she held him by the heel, so in the end an arrow found that heel and laid Achilles low.
Plasmodium falciparum is the poster pathogen of human malaria. That mosquito-borne parasite lays low more than a million victims a year, most of them children under 5, and strikes some 300 million to 500 million people with its debilitating infection. P. falciparum has two treacherous tricks going for it: The wily Plasmodium deploys increasing drug resistance against the arsenal of chemotherapeutic agents launched against it. And it virtually shrugs off the experimental antimalarial vaccines that keep coming down the pike.
Now a posse of scientists in France report discovery of P. falciparum’s Achilles’ heel, and a drug against it that cures infected monkeys. The current issue of Science, dated Feb. 15, 2002, describes this double-barreled feat under the title: “A class of potent antimalarials and their specific accumulation in infected erythrocytes.” The paper’s senior author is biochemist Henri Vial, who directs a joint laboratory between the University of Montpellier and France’s CNRS, the National Center of Scientific Research.
“The finding we report consists of two points,” Vial told BioWorld Today in a telephone interview. “The first one is that this paper refers to the outstanding antimalarial activity of our compound against human malaria in monkeys. That fulfilled our goal to completely cure primates. We cured monkeys highly infected with malaria in four days, with no recrudescence of the infection at 60 days. That means we killed all the Plasmodium parasites.
“The second point,” he went on, “is that the drug we discovered, which we call G25, is specifically accumulated inside the parasite’s target red blood cells that is, inside its victim’s infected erythrocytes. This explains why G25 is so potent and so selective, as we relate in the Science paper.”
Vial explained that when a mosquito touches down on its victim’s skin, the insect stabs it with its hollow, needle-like proboscis. While it sucks the blood it seeks, its saliva dribbles Plasmodium parasites into the wound. These head straight for their prey’s liver, where they proliferate sporozoites by the thousand. They break out a week later as merozoites the target of Vial’s G25 drug and attack the erythrocytes in the bloodstream. Each merozoite spawns a score of progeny, which rupture still more red blood cells. This vicious chain reaction causes the symptoms of human malaria severe anemia, fever, convulsions, coma and death.
Site of Vulnerability: Cell Membranes
Vial sums up Plasmodium’s Achilles’ heel in one word: “membranes.” He said, “The background is that the malarial parasite needs a huge amount of membranes, which is a tissue composed of phospholipids. So the questions for us were two: Where do these phospholipid molecules come from? And can we prevent the parasite from getting them? The first answer: These molecules are synthesized by the parasite’s enzymatic machinery. And the answer to the second question is that if we can block these biosynthetic pathways, we can stop the parasite’s access to the membranes.”
Vial noted that membranes are ubiquitous in living organisms from vertebrates to bacteria. “We humans use membranes for ourselves,” he pointed out. “We have them in our lungs. Inside our livers there are cells that have membranes, which are composed of lipids. Plasmodium falciparum needs a tremendous amount of membrane just for its use in cell culture. The pathogen’s cells have membranes from their mitochondria, from their nucleus, from their vasculature and so on. What we know,” he continued, “is that after infection, the phospholipid content of the infected erythrocytes is increased at least fivefold. That represents new membranes an attractive chemotherapy target.”
His team’s G25 compound acts against this parasitical Achilles’ heel, Vial explained, “because it’s an analogue of choline. We synthesized 400 such compounds, and chose the best one G25. Its function is to stop the biosynthesis of those membranes’ natural phospholipid. Choline is a precursor of the parasite’s major phospholipid that is, phosphatidycholine, which is a building block of membranes. G25 is an analogue that mimics choline, which it prevents from entering the infected erythrocyte.”
The parasite’s defenses were down, Vial proposed, because of their need to package each of their infected erythrocyte-born offspring in protective lipid membranes. Uninfected red blood cells, in contrast, had no need to synthesize such membranous sheaths. “By targeting this membrane synthesis,” Vial observed, “in theory we would be attacking metabolism that is not present in the host cell, which it would not affect. But if you prevent the parasite itself from synthesizing lipids, it will not survive.”
New Drug Cured Monkeys Quickly, Durably
He and his co-authors put this concept to the test in two primates severely infected with malaria by Plasmodium Old World Cynomolgus monkeys from the Philippines and New World Aotus monkeys from Colombia. Treated with injections of G25 at doses far lower than those of current antimalarials, the animals were quickly and totally cured of their malarial infections. “We tested our G25 compound in these two animal models against parasites resistant to quinine, chloroquine, pyrimethamine and Fansidar [which combines two antimalarial drugs],” Vial recounted. He expressed no concern over the possible development of drug resistance to G25. “This is not in the Science paper,” he said, “but we have used drug pressure for 10 months, and there was no resistance to G25 but we don’t know why.
“Now we are trying, with some success,” he went on, “to develop new compounds small molecules that can be orally delivered. They are close to G25, which must be given by injection. We have already tested one such orally available molecule in the monkeys.
“We hope that in the next four years,” Vial predicted, “we can start human tests but not before. First we will have to choose the best candidate compound, then conduct two years of preclinical safety and efficacy studies in animals.” Vial’s CRNS unit “has three patents pending. Now we have discussions ongoing with a pharmaceutical partner,” he concluded, “and I think we may have a commercialization agreement very soon.”