With the major news outlets the only source of information for many, one could hardly be faulted in presuming that the Zika virus was a modern scourge slated to annihilate the human race. Unfortunately, there is a mosquito-borne disease that currently afflicts close to 400 million people worldwide—estimated to have killed half the human population since the Stone Age. Malaria is a parasitic infection that kills close to 1 million people annually and is caused by the protozoan parasite in the genus Plasmodium.    

Five species of the plasmodium parasite cause malaria infections, with Plasmodium falciparum being the most virulent. The P. falciparum parasite is spread to humans through the bite of the female Anopheles mosquito and in recent years has grown increasingly resistant to the main antimalarial drugs.

Now, an international team of researchers led by scientists at the University of California, San Francisco (UCSF) has provided new evidence showing that some members of a class of compounds called oxaboroles, which contain the element boron, have potent activity against malaria parasites.

“We demonstrated that certain oxaboroles, selected from a large library produced by collaborating chemists, had potent activity both against cultured malaria parasites, and in an animal model of malaria,” explained senior study author Philip Rosenthal, M.D., professor in the department of medicine at UCSF. “New antimalarial drugs, ideally directed against novel targets, are greatly needed.”

The research team was able to gain insight into the mechanism of action of the compounds, knowledge that could be important for refining new antimalarial drugs based on oxaboroles. Moreover, they were able to demonstrate that the mechanism of action likely involves an enzyme required for protein synthesis. The investigators were able to accomplish this by growing the malaria parasites in the laboratory and treating them over generations with the oxaboroles. With time and generations, the parasites became increasingly resistant to the oxaboroles.

The researchers subsequently performed whole genome sequencing, both on the resistant parasites and on the original nonresistant P. falciparum, which had been stored for this comparison. They used the sequences to look for mutations in the resistant parasites that were absent from the nonresistant ones. “We consistently found them in this one gene,” Dr. Rosenthal noted. That gene—involved in parasite protein synthesis—is called leucyl tRNA-synthetase (LeuRS).

The interaction between the oxaboroles and the LeuRS enzyme is presumably what inhibits that enzyme, killing P. falciparum. As for the resistance to oxaboroles that developed in the lab, Dr. Rosenthal stated that it did not mean resistance would develop under clinical conditions, adding that “you can select for just about anything in the lab.”

“To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with step-wise increases in the concentration of AN6426,” the authors wrote. “Resistant clones were characterized by whole genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function.”

The findings from this study were published recently in Antimicrobial Agents and Chemotherapy in an article entitled “Anti-Malarial Benzoxaboroles Target P. falciparum Leucyl-tRNA Synthetase.”

“Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [14C]leucine incorporation by cultured wild type, but not resistant parasites,” the authors stated. “The growth of resistant, but not wild-type parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites.”

While this research is an important first step, the investigators noted that developing antimalarials is particularly challenging. “In addition to obvious requirements for safety and effectiveness, antimalarial drug candidates should meet additional criteria, including rapid clinical response, requirement for no more than 3 days of treatment (and ideally single-dose treatment), oral bioavailability, low tendency to select for drug resistance, lack of cross-resistance with existing antimalarials, safety in children and pregnancy, and low cost of production.”

Oxaboroles appear promising on all counts. Among other things, safety of the general class has been demonstrated even in human trials of class members, though for purposes other than as antimalarials. Oxaboroles are also not difficult to synthesize, which would make them relatively inexpensive.







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