Sponge-derived natural products lead to new antimalarial

Antimalarials discovered over the last century have proved effective in fighting malaria. But the parasites that cause the disease often develop resistance to these drugs, leaving a demand for new options.

Scientists have discovered a small molecule that suppresses malaria-causing parasites in vitro and in humanized mice by targeting a key parasitic organelle. The parasites also struggled to develop resistance to the compound, which the researchers say could make it a promising antimalarial candidate (Science 2024, DOI: 10.1126/science.adm7966).

Isocyanoterpenes are a family of natural products that are found in marine sponges. Many compounds belonging to the family have antibacterial, antifungal, and antimalarial properties. But the compounds are often complex and difficult to synthesize, leading chemists to search for simplified analogs that are easier to produce in the lab.

Chris Vanderwal, an organic chemist at the University of California, Irvine, was part of a team that first synthesized an antimalarial isocyanoterpene compound called kalihinol B. He and his team found that when they simplified kalihinol B, the resulting small molecule—which the team dubbed MED6-189—retained kalihinol B’s antimalarial properties.

The researchers tested MED6-189 against isolates of Plasmodium falciparum—the predominant malaria-causing parasite in humans. MED6-189 inhibited the growth of normal and antimalarial-resistant P. falciparum in vitro. Further tests showed that the compound also worked against two other Plasmodium species.

A fluorescent probe attached to the compound and drug-drug interaction tests with other antimalarials revealed that MED6-189 targets the apicoplast, a parasite-specific organelle wherein fatty acids and other essential molecules are synthesized. Transcriptomic, metabolomic, and proteomic analyses suggest that the compound may interfere with several molecular pathways essential to the parasite’s survival. MED6-189 was also effective in infected mouse models that were designed to circulate human blood.

Parasites can develop resistance to small-molecule antimalarials in just a few weeks in vitro. But it took about 36 consecutive months of drug pressure for P. falciparum to develop tolerance to MED6-189.

“After many failed attempts, we managed after 3 years to get a barely resistant parasite,” said Karine Le Roch, a biologist at the University of California, Riverside, who coled the study. “That was most likely due to the fact that the compound targets much more than one enzyme, one pathway.”

The scientists will now aim to test the compound’s effectiveness in nonhuman primates. They will also attempt to further simplify MED6-189 because they say the current synthesis is not cost-effective. Vanderwal and Le Roch added that continuing to study the molecule’s mechanism of action could help them design similar antimalarials that target specific molecular pathways.

“This work is a powerful demonstration of the importance of natural products for biological discovery. But more than that, it shows how the natural product itself is only a starting point, not the end goal, of synthesis,” Ryan Shenvi, a synthetic chemist at Scripps Research who was not involved in the work, writes in an email. “The kalihinols have attracted the community for years, but Vanderwal’s MED6-189 shows how to wield that magnetism productively.”