May 18, 2021

Achieve a 'map' with 631 "promising" chemical compounds against malaria

Achieve a 'map' with 631 "promising" chemical compounds against malaria



Most anti-malarial drugs are designed to reduce symptoms after infection, but they do not prevent it. Now, an international consortium of researchers has managed to gather a set of 631 "promising" compounds that could form the basis of new drugs.

The scientists, led by Elizabeth Winzeler of the University of California (San Diego, USA), looked for these molecules in a "chemical library" of more than 500,000 compounds.

After two years of research, the experts chose those – a total of 631 – capable of eliminating the malaria parasite at a very early stage of its life cycle, when it first takes root in the liver; Attacking this "liver phase" prevents the parasite from developing, reaching the blood and causing malaria.

The results of this "chemical map", whose data will be shared openly with the entire scientific community, are published in the journal Science, in an article also signed by Spanish researchers.

The drugs currently in clinical use, mostly, work by blocking the replication of blood parasites that cause the disease in humans – "Plasmodium falciparum" and / or "Plasmodium vivax", mainly – but do not prevent infection or transmission, notes in a note the University of California, which warns that they have also developed resistance to most drugs.

Hence the need to continue researching. In Winzeler's words, the search for new anti-malarial drugs has been, in many ways, similar to aspirin: it makes you feel better but it does not necessarily go after the root of the problem.

Therefore, adds the scientist from the University of California, this work adopts a different approach: to address the malaria parasite at an earlier stage of its life cycle – hepatic phase.

This life cycle begins when an infected mosquito transmits sporozoites – the parasite in its early stages – to a person. Some can establish an infection in the liver and, after replicating in this organ, they pass into the blood and infect the red blood cells.

It is then when the person begins to experience the symptoms of malaria: fever, chills and headaches in its most benign form, but this can even cause death.

And it is also when the parasite can be absorbed by a new mosquito and complete its life cycle to be transmitted to another person.

The scientists worked with a million mosquitoes, which, for safety and pragmatism, infected with a type of parasite, "Plasmodium berguei", which can only produce malaria in mice, not in humans.

The mosquitoes were infected at the facilities of the Columbia University Medical Center in New York and then sent every Tuesday for two years to the Winzeler laboratories in California, where mosquito sporozoites were extracted and transferred to plates with liver cell lines. be examined and test compounds.

These sporozoites are able to invade that cell line and develop inside it.

According to Francisco Javier Gamo, director of biology at the Global Health unit of GSK in Tres Cantos (Madrid) and one of the authors of the study, the trial consisted of using genetically modified P. berguei sporozoites that are capable of express a protein called luciferase that literally produces light under certain conditions.

The objective is to read the plates with a luminometer that detects the signal produced by luciferase.

"This process was done in independent wells for each of the 500,000 molecules tested and in those cases where the compound was effective against the parasite, no luciferase was produced and the compound was labeled as positive."

In a later analysis, the toxicity of those marked as positive -in light absence- was examined, in order to identify those that did not damage hepatocytes (liver cells).

"This set the set of 631 compounds that can serve as a starting point to start projects of discovery and development of drugs," says Gamo, who adds that the next step will be to optimize the physicochemical and biological properties of these molecules and select the best candidates for, in the future, to become preventive antimalarials.

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