Molecules known for their anti-cancer activity have proven effective in combating Plasmodium falciparum, the parasite that causes malaria. Researchers at the University of São Paulo's School of Pharmaceutical Sciences (FCF-USP) in Brazil also investigated how differences in the structure of these molecules affect their impact on the parasites. This research paves the way for the development of more effective drugs.
According to estimates by the World Health Organization (WHO), malaria was responsible for approximately 600,000 deaths in 2024. Célia Regina da Silva Garcia , a professor in the Department of Clinical and Toxicological Analysis at FCF-USP, says that an estimated 90% of these deaths are caused by P. falciparum. Although treatments for malaria already exist, the parasite has become more resistant to drugs such as chloroquine and artemisinin, making the development of new treatments necessary. In this context, repurposing drugs already used for other purposes emerges as a faster, cheaper alternative in the search for new therapeutic approaches.
The research was funded by FAPESP (projects 17/08684-7 , 21/06607-0 , 23/07656-0 , 24/07723-2 , 22/15522-1 , 24/09115-0 , 24/06392-2 , 22/07275-4 , and 23/07455-5 ). Fourteen compounds derived from an antineoplastic drug (used to treat cancer) were tested on P. falciparum parasites cultured in the laboratory. The results showed that the molecules were effective in eliminating the microorganisms at two different stages of development: the asexual and gametocyte stages.
By eliminating the parasite in the asexual stage, when it reproduces in blood cells and causes the fever typical of malaria, the new drugs show great potential for treatment. Additionally, the molecules act during the gametocyte stage when Plasmodium infects mosquitoes. Thus, in addition to treating the patient, the medication can block the transmission of the disease.
Side effects
Despite the promising results published in July in the journal ACS Omega, there are concerns about the possible side effects of these molecules. Since only in vitro tests have been conducted thus far, the extent of the problem has not yet been assessed. Some of the tested compounds showed reduced efficacy in tests with human cells while maintaining their effect on the parasites. This indicates a lower risk of serious adverse effects. However, only in vivo tests can confirm this. "Molecules in that class can cause fatigue, nausea, vomiting, and hematological changes, such as a decrease in platelets. It's natural for that concern to exist," says Garcia. In vivo tests are also important for verifying the ability of drug candidates to remain stable in a patient's body since drugs in this class tend to degrade rapidly under these conditions.
To overcome these limitations, Garcia's team analyzed how variations in the structure of different derivatives affect their function, as well as the target of these derivatives within the parasite's cell. This makes it possible to plan the development of new drugs with characteristics better suited for treatment. "When we engage in rational drug design of new molecules, we can refine their chemical structure in a targeted manner. Our experiments have strengthened the hypothesis that histone deacetylase enzymes are an important therapeutic target for malaria. As a result, we've been able to design new molecules that are increasingly potent and selective against the parasite," Garcia explains.
Another future goal of Garcia's team is to test the molecules on other malaria-causing parasite species, such as Plasmodium vivax, which is prevalent in Brazil and can cause relapses even after treatment. "P. vivax can also develop latent forms known as hypnozoites that lodge in the liver. Furthermore, it's more widespread in equatorial countries. Therefore, it's important to evaluate the efficacy of antimalarial drugs against different species to ensure they're effective in various regions of the world," says Garcia.
About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.
