Because of its safety, efficacy, and affordability, chloroquine remains the treatment of choice for all Plasmodium species, except in regions with chloroquine-resistant P. falciparum. Chloroquine-resistant protists are treated with combination therapy, which includes artemisinin-derived molecules in some cases. But one drug is easier to administer than two, and scientists working on chloroquine resistance have found a clever mechanism that may lead to a new, two-birds-with-one-stone malaria treatment.
The work comes from a collaboration between two groups led by Brian Dymock and Kevin Tan. Tan’s group had previously identified novel chemosensitizers – compounds that revert malaria parasites to chloroquine sensitivity. This is not a new effort, but one that’s met little success, with identified compounds performing well in vitro but poorly in vivo. The previous screen found seven new chemosensitizers that lowered sensitivity of most tested strains (see figure, left). The most recent studies, focusing on molecular hybrids of chemosensitizers and drugs, are now available in Antimicrobial Agents and Chemotherapy.
First author Aicha Boudhar and the team of scientists reasoned that only certain molecular structures of the chemosensitizer molecule would play a functional role in the resensitization, just as only certain molecular structures of chloroquine play a functional role in P. falciparum inhibition (see figure, right), which works by hindering heme detoxification in the Plasmodium vacuole. Resistant strains have modified pfCRT (P. falciparum chloroquine-resistance transporter) are able to pump out the drug before it accumulates to toxic levels. The researchers generated nearly 50 hybrid compounds combining the previously-characterized chemosensitizers and chloroquine.
These hybrid compounds were then tested for efficacy of Plasmodium inhibition (see figure, below). The compounds were tested on seven strains of various drug resistances – both sensitive and resistant to chloroquine, and some multiple drug resistant strains as well. Two hybrid compounds, dubbed 27a and 35, proved effective against all strain backgrounds, showing therapeutic promise without the need for strain typing. These data also demonstrate that clinically relevant strains, such as the multidrug resistant strains seen in some parts of the world, might be treated effectively, regardless of their resistance profile.
Compounds 27a and 35 are therefore promising future treatments, but do need more verification in animal models to assure its safety. Both liver cell and cardiomyocyte cell lines required a much higher dose to initiate any cell toxicity – over 100-fold for the liver cells – suggesting that a good therapeutic window exists. Animal studies will elucidate the compound’s bioavailability, biological half-life, and other relevant pharamacokinetic characteristics.
Malaria affects over 200 million people worldwide, leading to 438,000 deaths annually. Chloroquine was once hailed as a way to eliminate malaria, but chloroquine resistance has stymied the treatment of choice, especially in (area). With the recent Nobel Prize for Youyou Tu, malaria and other tropical diseases were brought to the forefront of scientific attention. With luck and hard work, new drugs (and in this case, hybrids using old drugs) will enable the quick and easy treatment of those suffering even drug-resistant malaria.
-- Julie Wolf