Scientists have discovered a series of a novel compound (bicyclic azetidine series) that shows great promise in the battle against malaria.
Four candidate agents were characterised and one compound was found to act on all three life stages of the malaria parasite.
The compound was found to cure the disease with just a single, low-dose treatment, provide prophylaxis and prevent disease transmission both in the lab and in animals. The prophylactic effect lasted for as long as 30 days in mice.
The compound had activity against a number of malaria-causing Plasmodium strains with a variety of resistant mechanisms.
Researchers from Broad Institute of MIT and Harvard, New Delhi’s International Centre for Genetic Engineering and Biotechnology (ICGEB) and other institutions published the results of their study on September 7 in the journal Nature .
“A single, low-dose is able to target the parasite so very effectively due to the high potency of the compound and by targeting an essential cellular function in the malaria parasite,” Dr. Amit Sharma, one of the authors of the paper from ICGEB, said in an email to The Hindu . The compound has low metabolism, long half-life and good oral bioavailability.
One of the issues with malaria is the reappearance of the Plasmodium parasite (recrudescence). The parasite can persist for a few months in blood without causing apparent symptoms. “It was for this reason that we carried out 30-day studies with both P. berghei (a mouse strain) and P. falciparum (the parasite responsible for most malaria deaths worldwide). A dose of 25 mg/kg showed no recrudescence for 30 days that we monitored,” Dr. Nobutaka Kato, the first author of the paper from the Broad Institute of MIT and Harvard, said in an email to The Hindu . “No recrudescence for 30 days means we killed all the parasites.”
Effective at every stage
The compound was able to achieve extraordinary results in mice as it targets the parasite’s protein translation machinery (phenylalanine tRNA synthetase), which is the very core of the parasite’s housekeeping function of synthesising about 5,000 proteins. Protein translation is vital at every stage of the Plasmodium life cycle.
Since the target is so essential for the parasite’s functioning, it is quite unlikely that it would undergo mutations. So, there are less chances of the parasite developing resistance against the compounds. “In a standard tool for measuring for generation of resistance, we found a low propensity for resistance,” Dr. Marshall L. Morningstar, a co-author of the paper from Broad Institute of MIT and Harvard said in an email.
Addition of a highly potent drug component to the already very successful artemisinin combination therapy will go a long way in stemming malaria infections, and may present therapeutic options when artemisinin drug-resistance becomes a problem.
The team says that it would take 5-7 years before a potent drug becomes available for commercial use. “What is important is that there are now new molecules in the development pipeline and therefore we can expect more therapeutic arsenals against the parasite in the coming years,” Dr. Sharma says.
