A novel compound prevents, cures malaria

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The novel compound acts on all three life stages of the malaria parasite -Photo: James Gathany/CDC

In a pathbreaking discovery, scientists from New Delhi’s International Centre for Genetic Engineering and Biotechnology (ICGEB), Broad Institute of MIT and Harvard and other institutions have isolated a compound that is able to completely clear malaria parasites with just a single, low-dose treatment.

The compound acts on all three life stages of the malaria parasite, has prophylactic property and prevents disease transmission in mice. The prophylactic effect lasted for as long as 30 days. The compound had activity against a number of malaria-causing Plasmodium strains with a variety of resistant mechanisms.

The researchers found a series of novel compounds (bicyclic azetidine series) that shows great promise in the battle against malaria. Four candidate agents were characterised and one compound was tested in mice.

The results of the study were published 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 me. The compound has low metabolism, long half-life and good oral bioavailability.

Since the target is so essential for the parasite’s functioning, it is quite unlikely that it would undergo mutations.

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. “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.

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Broad Institute – Photo: Len Rubenstein

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 compound. “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.

“A lot of studies will be needed to ensure that the findings in mice get translated into humans. Fortunately, we have a great group of researchers spanning the globe to help us complete the necessary studies,” Dr. Morningstar says. 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.

DOS library

The Diversity Oriented Synthesis (DOS) library, from where the compounds were selected, is a unique collection of 100,000 chemical compounds that are not traditionally represented in pharmaceutical libraries and were designed to emulate small molecules found in nature. “By employing build/couple/pair strategy, the library was built utilising a variety of chemistry routes,” Dr. Kato says.

From this library, 478 compounds that had potent activity against chloroquine-resistant Plasmodium strain were identified. Compounds that targeted two common mechanisms of action in malaria were removed and those that showed in vitro inhibitory activity in gametocyte and liver stage assays were prioritised. “The bicyclic azetidine series was the lead series from this cascade effort,” Dr. Morningstar says.

“We have made all structures and screening data available online at a new Malaria Therapeutics Response Portal and invite the scientific community to use this database as a jumping-off point for other anti-malarial development efforts,” Dr. Kato says.

 

UPDATE (September 13, 9.30 am)

The Director-General of the Indian Council of Medical Research (ICMR) Dr. Soumya Swaminathan has shown interest in the study and tweeted saying: “ICMR will be happy to partner in further drug development and human trials.” Now that’s what is called a lightning response to a promising study.

Published in The Hindu on September 13, 2016

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