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Drug Discovery

Single dose of small molecule cures malaria in mice

Studies show the malaria parasite has a tough time developing resistance to the compound MMV688533

by Bethany Halford
July 21, 2021 | A version of this story appeared in Volume 99, Issue 27

Structure of MMV688533.

A small molecule can cure malaria infections in mice with a single dose, researchers report. They also show that the malaria parasite Plasmodium falciparum has a tough time developing resistance to the compound, known as MMV688533. If shown to be safe and effective in people, MMV688533 could be a powerful weapon in the fight against malaria.

Although malaria infections and deaths declined from 2000 to 2015, thanks to preventative measures, diagnostics, and therapeutics, the number of people who get malaria has plateaued since 2016.

Malaria parasites in southeast Asia have developed resistance to the current arsenal of antimalarial drugs, making them ineffective in many cases. This same resistance threatens to become a problem in Africa, where malaria makes the biggest impact.

Malaria killed about 409,000 people in 2019, according to the World Health Organization. “It could easily get a lot worse if we lose our first line drugs,” says malaria researcher David A. Fidock of Columbia University Irving Medical Center.

Fidock and Didier Leroy of Medicines for Malaria Venture led the international team that discovered MMV688533. They didn’t use the typical drug discovery approach of screening a vast compound library against a known antimalarial target. Instead, they started with a relatively small number of compounds from drugmaker Sanofi—roughly 800—that are active against human targets such as cancer-cell proteins. The researchers predicted that some of these compounds might hit targets with similar functions in the malaria parasite P. falciparum, and therefore might also be effective malaria treatments. They screened these compounds to see which ones killed P. falciparum. One hit, which turned out to be a dimer of a compound related to the anticancer drug candidate cariporide, looked promising. They tweaked this compound to improve its solubility and boost its ability to get into the intestines, arriving at their antimalarial candidate MMV688533 (Sci. Transl. Med. 2021, DOI: 10.1126/scitranslmed.abg6013).

MMV688533 can cure a P. falciparum malaria infection in mice with a single oral dose. Malaria parasites have a tough time developing resistance to the compound, and when they do, a higher dose can wipe them out. The drug candidate was also effective at killing malaria parasites that show resistance to existing antimalarial drugs.

Manuel Llinás, a biochemist at Pennsylvania State University who studies malaria parasites, says in an email that MMV688533 “is an exciting new lead as it is both fast acting and long-lasting with limited resistance developed in vitro, which are all promising preclinical features.” He adds that it will be important to figure out how the compound kills the parasite—something that Fidock and Leroy’s team don’t know yet.

Given MMV688533’s high potency and its ability to evade resistance, it’s possible that the compound hits multiple targets or a family of related targets, says Edward Tate, a chemical biologist at Imperial College who studies antimalarial compounds. “It is difficult to imagine how such a compound could be designed through a target-based approach,” he says in an email.

MMV688533 is currently in Phase 1 clinical trials in Australia to assess its safety and tolerability.


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