Uncovering Treasures In The Malaria Box

Researchers from Singapore and India jointly screened a collection of 400 chemically diverse small molecules for their efficacy against two pathogenic parasites.

AsianScientist (Feb. 2, 2018) – In a study published in mSphere, scientists in Singapore and India have identified compounds and sorted them according to their efficacy against the parasitic pathogens that cause malaria and toxoplasmosis.

Plasmodium falciparum parasites cause malaria and morbidly impact the economies of the developing world. Although asymptomatic and not as deadly as malaria, toxoplasmosis, caused by Toxoplasma gondii, can lead to serious health concerns in pregnant women and immuno-compromised individuals.

The WHO-supported Medicines for Malaria Venture (MMV) has a collection of 400 chemically diverse small molecules as the MMV ‘Malaria Box’ which may be useful in the treatment of the two diseases. However, the mechanisms by which these inhibitors kill the parasites remain largely unknown.

In this study, a team of researchers led by Assistant Professor Rajesh Chandramohanadas of the Singapore University of Technology and Design (SUTD), together with collaborators from the National Chemical Laboratory (NCL) in India, segregated the MMV box library based on the life-stage events affected by individual inhibitors. They achieved this using complementary phenotypic screens on P. falciparum and T. gondii, identifying phenotype-specific hits based on inhibition of overall parasite growth, apicoplast segregation and egress or host invasion.

The researchers identified 24 molecules with nanomolar potency against both parasites. 30 molecules were also found to cause delayed death in T. gondii, out of which three interfered with apicoplast segregation, an essential process for the formation of new daughter cells. The scientists also identified 26 molecules that specifically inhibited parasite release or host cell invasion of P. falciparum.

In addition, five of their ‘hits’ were active against the release of T. gondii parasites from mammalian cells, highlighting pathways that can be exploited in both parasites using the same class of molecules.

“Having completed the phenotypic characterization and stage-specificity studies, we have now shortlisted a handful of excellent inhibitors for detailed mode-of-action and medicinal chemistry studies towards novel drug development,” said Chandramohanadas from SUTD.

“Egress and invasion are highly similar between malaria and toxoplasma parasites. Therefore, identification of molecules that affect both parasites during their release from infected host cells not only highlights robustness of the complementary screening approach we adopted, but also identifies conserved drug targets for pan anti-parasitic drug development,” said Dr. Dhanasekaran Shanmugam from NCL.



The article can be found at: Subramanian et al. (2018) Targeted Phenotypic Screening in Plasmodium falciparum and Toxoplasma gondii Reveals Novel Modes of Action of Medicines for Malaria Venture Malaria Box Molecules.

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Source: Singapore University of Technology and Design.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

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