A new single-dose malaria treatment could save 500,000 lives and help 200 million people. A study published recently in Nature identifies new compounds to fight the malaria parasite, Plasmodium falciparum.
Researchers from the Broad Institute of MIT and Harvard, headed by Stuart Schreiber, scoured a library of 100,000 chemical compounds for something that met the required criteria: targeting the parasite in a novel way and working during all three stages of its life (liver, blood, and transmission). These compounds were then tested on mice, and they successfully eradicated the malaria parasites during all three stages with one low dose. All of the 100,000 compounds in the library and the data from the team’s malaria screens are publicly available via the Malaria Therapeutics Response Portal (MTRP).
ResearchGate: What sort of challenges does malaria present when looking for treatments?
Nobutaka Kato & Eamon Comer: The malaria parasite is challenging because it has developed resistance to the standard-of-care drugs, including first-line therapies. To overcome this, antimalarials with new mechanisms are needed that are unaffected by existing resistances. Also, the majority of current drugs only target the symptomatic blood-stage parasites. Malaria parasites have liver- and transmission-stages that do not cause symptoms. Despite this, prophylaxis and transmission-blocking drugs are essential to prevent epidemics and protect vulnerable populations such as such as pregnant women and children under the age of five. Antimalarial drugs that target all stages of the malaria parasite are very much needed.
RG: What were the results of your study? What makes your treatment different from existing treatments?
Kato & Comer: We identified a series of bicyclic azetidine compounds that inhibit the malaria parasite in a new way, inhibition of phenylalanyl-tRNA synthetase, which blocks parasite protein synthesis. These bicylic azetidines provide single low-dose cures and work against all stages of the malaria parasite, in multiple in vivo efficacy models. While rigorous safety analysis and optimization will be needed, our findings identify compounds with the potential to cure and prevent transmission of the disease as well as protect populations at risk, all in a single oral treatment.
RG: Can you give us a brief insight into how you found the compounds?
Kato & Comer: Antimalarial drugs have thus far originated mainly from two sources – natural products and synthetic ‘drug-like’ compounds. We suspected that new antimalarial agents with new action mechanisms could be discovered using our unique collection of 100,000 Diversity Oriented Synthesis (DOS) compounds. These compounds have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. DOS compounds that showed signs of operating through a novel mechanism in malaria phenotypic screens were prioritized for advanced studies. We then prioritized compounds further by applying a second criterion: we looked for compounds that appeared to work in all stages of the malaria parasites’ life cycle. Finally, we prioritized compounds most likely to have the properties necessary to become antimalarial drugs.
RG: What are the next steps in your research? Do you expect any challenges when taking this from mice to people?
Kato & Comer: We need to rigorously assess the safety of the bicyclic azetidine series and address any liabilities uncovered before initiating a human clinical trial. This process is ongoing.
RG: When do you hope to have treatment options available to people?
Kato & Comer: Typically, a potential medicine for an infectious disease should take about twelve years on the journey from the first hypothesis to registration. We hope to initiate clinical trials with the series within the next four years.
RG: What does your study mean for the malaria research more generally?
Kato & Comer: From the point of view of modern synthetic organic chemistry this study shows that different chemistry yields different outcomes when applied to problems of microbial pathogens. This study also resulted in an open, data-rich resource for the malaria research community called the Malaria Therapeutics Response Portal (MTRP). This includes a trove of information on highly active compounds that is available to the scientific community to use for developing new antimalarial therapies.