Molecules isolated from natural products are strategic to combat neglected diseases

The point was stressed by participants in the 6th FAPESP 60 Years Conference, featuring experts from Brazil, the UK and the US who discussed the search for drugs to treat diseases that affect some 2 billion people worldwide.

By André Julião  |  Agência FAPESP – Relations among organisms in nature involve the production of a series of compounds that serve to combat adversaries, among other functions. Plants, fungi and bacteria are some of the organisms known to produce such substances, which the pharmaceutical industry has used for a long time in medications to treat various ailments but which are now being increasingly explored in the search for drugs to treat neglected tropical diseases (NTDs). This was the focus for the 6th FAPESP 60 Years Conference, held on November 17. The event was recorded and can be watched on YouTube.

“Neglected diseases strongly affect the poorest regions of the planet, especially tropical and subtropical regions, which mostly have low human development indices. Malaria, leishmaniasis, Chagas, dengue and Chikungunya are examples of neglected diseases found in Brazil. The people affected by these diseases are not a profitable market for Big Pharma, which doesn’t invest enough in drug development to treat them,” said Ronaldo Aloise Pilli, Vice Chairman of FAPESP’s Board of Trustees and a professor in the Institute of Chemistry at the University of Campinas (UNICAMP), in his welcoming remarks to participants in the event. Several public-private initiatives have been launched since the 2000s to accelerate research and development in this area of public health, he added.

The World Health Organization (WHO) lists 20 NTDs caused by bacteria, fungi, parasites, and toxins. They affect some 2 billion people worldwide, leading to high mortality and permanent incapacity among men, women and children.

“The next decade will be crucial for the future of the global response to these diseases. Progress toward the goals set by the WHO for 2030 must be constantly reviewed so that the global response is able to move ahead in addressing the related health and development challenges, in step with efforts to achieve the UN’s Sustainable Development Goals,” said the mediator Adriano Andricopulo, a professor at the University of São Paulo’s São Carlos Institute of Physics (IFSC-USP).

Malaria and Chagas

“Even though these diseases affect 11% of the world population, only one novel chemical entity, fexinidazole, has been approved this century for treatment of a specific NTD, human African trypanosomiasis [also called sleeping sickness],” said Glaucius Oliva, a professor at IFSC-USP and principal investigator at the Center for Innovation in Biodiversity and Drug Discovery (CIBFar), a Research, Innovation and Dissemination Center (CEPID) funded by FAPESP. 

Oliva presented some of the projects in progress at CIBFar with NTDs as their focus. One such project, led by Andricopulo, is looking for inhibitors of cruzain, an enzyme present in Trypanosoma cruzi, the parasite that causes Chagas.

Another initiative discovered potential inhibitors of Plasmodium falciparum and P. vivax, parasites that cause malaria. P. vivax is responsible for most cases in Latin America. The likely inhibitors include marinoquinolines, originally isolated and identified in marine bacteria. The project involves collaboration with several Brazilian and foreign groups, including the Medicines for Malaria Venture (MMV), a global nonprofit that focuses on delivering affordable and accessible drugs for use in malaria-endemic areas.

Mike Ferguson, Regius Professor of Life Sciences at the University of Dundee (UK) and a member of the Wellcome Center for Anti-Infectives Research (WCAIR), is participating in a team that has tested a malaria drug candidate in clinical trials. The results have been promising with a single dose, and Phase 2 trials have been scheduled for this year and next. Ferguson stressed the contribution of projects involving natural products to drug discovery and the identification of other molecular targets.

“If you have a natural product which has been shown to be effective in killing the trypanosomes, for example, and then you identify the molecular target, you can start a small molecule discovery program against that target because it has been validated by a natural product,” he said.

Fungi and ants

While potential treatments for these diseases are making progress, the situation in fungal diseases worsens every year. Few medications exist to combat fungi, which are highly capable of developing drug resistance. They cause many deaths and novel therapies are urgently needed.

“Systemic fungal infections can be life-threatening. The number of cases is relatively small, but mortality rates are extraordinarily high. The death rate for COVID-19 is probably at most 1% or 2%, but for fungal infections, it ranges from 30% to 95%. As many if not more people die from invasive fungal infections than from tuberculosis or malaria,” said Jon Clardy, Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School in the United States.

Leaf-cutting ants offer hope. Some species that evolved 50-60 million years ago grow fungus for food, but their survival depends largely on their capacity to combat another fungus, which would otherwise destroy their stores of food. 

In a project funded by FAPESP and the US National Institutes of Health (NIH), Clardy and Monica Tallarico Pupo, a professor at the University of São Paulo’s Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP), described a new chemical entity, attinimycin, present in bacteria that colonize the bodies of these ants in a second mutualism: the bacteria produce antibiotics that help defend the ants’ “gardens” against fungal pathogens, and the ants feed the bacteria. 

As Pilli stressed in his opening remarks, “neglected diseases are one of the cruelest facets of social inequality. Medicinal chemistry, in conjunction with synthetic chemistry, has a key role to play in the fight against these endemics”.

A recording of the complete event is at: youtu.be/SeJdnfHnkuc. 

The first five FAPESP 60 Years Conferences are at: 60anos.fapesp.br/conferencias.