Diversity-oriented synthesis leads to a promising new compound for the single-dose treatment of malaria.

I wonder what your answer would be if you were asked “What is the world’s deadliest animal to humans?” Perhaps a venomous snake, a great white shark, or one of the big cats. You might be surprised to find out that the answer is, in fact, the mosquito, responsible for 830,000 deaths in 2015. The reason for the mosquito’s infamy is, of course, that it is responsible for the transmission of malaria via the plasmodium parasite.

Although the death rate from malaria has been halved over the last 15 years, there is still a pressing need for new and improved treatments, not least because mosquitoes are becoming resistant to the current generation of artemisinin-based combination therapies. The ideal drug would eliminate all three stages of plasmodium parasite infection in humans (i.e., the blood, liver and transmission stages). Recently, an international group of academic and industrial researchers has reported some promising research in the journal Nature that may ultimately deliver just such a drug.

The group used diversity-oriented synthesis, inspired by natural products, to generate a library of approximately 100,000 compounds with structures not commonly found in traditional screening collections. These were tested in an initial high-throughput screen based on the human blood-stage of infection. Compounds found to be active in this assay were then tested for their effectiveness in screens based on the liver and transmission stages. This screening cascade resulted in the identification of four novel series of molecules for further evaluation.

Three of the four hits were found to act at known anti-malarial targets, but the fourth (denoted BRD3444 and shown at right) appeared to work by an entirely new mechmalariaimage1anism. Subsequent target identification investigations revealed that this so-called bicyclic azetidine inhibits a previously unknown antimalarial target: cytosolic phenylalanyl-tRNA synthetase. 

BRD3444 itself was quite poorly soluble and subject to rapid metabolism but these shortcomings were addressed by a small change to the structure resulting in BRD7929, which has properties making it suitable for single dose oral treatments.

BRD7929 was tested in two mouse disease models and was shown to eliminate blood- and liver-stage parasites suggesting that this class of compound has the potential to cure the disease, provide prophylaxis and prevent disease transmission. While further optimization of this class is likely to be required before a compound suitable for human trials can be selected, these are nonetheless very exciting findings that may help in the ongoing battle against this deadly disease.

How to Cite:

Clark, David. Facing Down the World’s Deadliest Animal. Eureka blog. Nov. 21, 2016. http://eureka.criver.com/facing-down-the-worlds-deadliest-animal/