As the world struggles with the Covid-19 pandemic, a set of 20 diseases known for many years, but still without effective treatments or vaccines, kills up to 500,000 people a year, the vast majority of whom are poor.
The fight against so-called neglected tropical diseases (NTDs), which affect one in five people, has won a new action plan from the World Health Organization (WHO), with targets to be met by 2030.
In addition, as a way of engaging the public in the cause, more than 300 organizations celebrated, on January 30, the World Day for Neglected Tropical Diseases.
The eradication or even the reduction of cases of these 20 diseases, which include leishmaniasis, Chagas disease, dengue and zika, necessarily involves understanding the infectious agents and developing safe, effective and accessible medicines and vaccines. For this reason, experts point out that investment in research and development is essential.
“Today there are more than 1.7 billion people in the world affected by these diseases, which cause not only deaths, but a great morbidity, taking many years of life from those who survive. Brazil, which gathers a large part of the 20 neglected tropical diseases, is a leader in Latin America in cases of Chagas disease, leishmaniasis, leprosy, dengue and schistosomiasis ”, said Adriano Andricopulo, professor at the São Carlos Institute of Physics at Fapesp University of São Paulo (IFSC-USP).
The researcher coordinates the project “Discovery of drugs based on the structure of the receptor and ligand for Leishmaniasis and Chagas Disease from bioactive natural products”, funded by Fapesp and the Medical Research Council, from the United Kingdom, in partnership with Dundee University, Scotland.
Andricopulo is also a researcher and technology transfer coordinator at the Center for Research and Innovation in Biodiversity and Pharmaceuticals (CIBFar), a CEPID supported by Fapesp at IFSC-USP. Currently, the group has ten candidates for Chagas medicine and about 20 for leishmaniasis.
CIBFar is part of the consortium formed by USP and the State University of Campinas (Unicamp) for the discovery of drugs against malaria and neglected diseases. Financed by Fapesp and by the non-profit organizations Medicines for Neglected Diseases Initiative (DNDi) and Medicines for Malaria Venture (MMV), the project is part of Fapesp’s Partnership for Technological Innovation Research Support Program (PITE).
The consortium’s objective, signed at the end of 2020, is to develop molecules that could be candidates for clinical tests for leishmaniasis, Chagas and malaria. Article
The latter is not part of the WHO list of 20 neglected tropical diseases, since it already has pharmacological alternatives and even a vaccine, although with an efficacy of about 30% in four doses.
“I usually say that malaria is not a neglected tropical disease, but it is a disease that affects neglected people”, says Luiz Carlos Dias, professor at the Institute of Chemistry (IQ) at Unicamp and project coordinator.
According to WHO data, in 2018 malaria killed 405,000 people, 67% of them children under the age of five.
The parasite is known to quickly build up drug resistance. And those currently available need to be administered in three doses or more.
For this reason, the group led by Dias is looking for a drug that is safe for children and pregnant women, the most vulnerable groups, and that can be administered orally in a single dose. In the case of Chagas’ disease, since there are currently no good pharmacological options, the group admits an alternative that is divided into more doses.
The challenges are immense. At different times we had very promising chemical series, but as the tests progress we discover a possible adverse effect. When this occurs, we make adjustments, but this can generate another unwanted effect, such as loss of effectiveness, for example. There comes a time when it is better to rule out the possibility and start all over again with another chemical series. It is a very long ruler to which we submit ”, explains the researcher, who currently conducts in vitro tests for both malaria and Chagas disease.
Lessons from the pandemic
For Dias, the Covid-19 pandemic has shown how long-term investments, information sharing and qualified human resources make a difference in the fight against infectious diseases. In addition, combating the new coronavirus has shown that it is possible to accelerate the development phases of drugs and vaccines without decreasing safety and effectiveness.
“Brazil has exceptional scientists and a lot of installed capacity, but in recent years it has lost a lot of research funds.
The pandemic has shown the importance of massive and continuous investments, in addition to a national pharmaceutical industry. Today we are very dependent on India and China, especially for these products, ”says the researcher.
For Charles Mowbray, director of research and development at DNDi, one of the funders of the consortium, in addition to the faster development of medicines and vaccines, the pandemic showed the need for multiple parallel approaches, such as medicines and vaccines, to face challenges such as resistance and new variants of pathogens.
“We still have to ensure that new advances that apply the latest technologies are made available to everyone who needs them, not just those who can afford them”, points out the scientist.
Andricopulo believes that there would already be therapeutic solutions for most of the neglected tropical diseases if there were a mobilization similar to the one that is now taking place to combat the COVID-19 pandemic. “However, investments in research in this area are very limited. In the 21st century, no innovative medicine was produced for any of the 20 neglected tropical diseases. This is a big problem ”, he says.
In recent years, however, nonprofit initiatives like DNDi and the Bill & Melinda Gates Foundation have invested in the search for cheap and effective drugs against these diseases.
The USP researcher also recalls measures to encourage the pharmaceutical industry, which historically has not invested in the development of drugs for these diseases because they have no expectation of profit. New drug development projects in this area take into account that they must be donated or sold to governments at cost.
Since 2008, the Food and Drug Administration (FDA, the American agency that regulates medicines) has reduced the time to release potentially lucrative drugs (for cancer or cardiovascular diseases, for example) by up to one year if the company that submitted the order makes investments in research for neglected diseases.
It is impossible to develop drugs, however, without understanding the agents that cause disease, that is, viruses, bacteria and parasites. Projects financed by Fapesp in recent years have sought to carry out this work, some in collaboration with international partners such as the Medical Research Council and Newton Fund, from the United Kingdom.
An example is the Brazil-United Kingdom Center for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE), a project coordinated by Ester Sabino, professor at USP’s Institute of Tropical Medicine (IMT). Originally intended for the study of diseases such as dengue and zika, CADDE has also been instrumental in combating the new coronavirus.
The agreement with the United Kingdom is a very successful experience, which is even being extended. We had calls at specific times and they are now in continuous flow. That is, at any time of the year researchers from the State of São Paulo can submit proposals in collaboration. Today we have several networks, with important people from Brazil and the United Kingdom, forming groups in which there is an increasing respect for the Brazilian scientific community ”, says Angela Kaysel Cruz, professor at Ribeirão Preto Medical School (FMRP-USP) and coordinator of Biology II at Fapesp.
The researcher served as a member of advisory committees and working groups of the WHO Tropical Diseases Research Division between 1997 and 2006. She currently coordinates the UK-Brazil Center for the Study of Leishmaniasis (JCPiL), which has different lines of research on the parasite that causes the disease, such as understanding genetic diversity, virulence, resistance mechanisms, among others.
The parasites of leishmaniasis, sleeping sickness and Chagas disease are all from the same family, but they have very different behaviors. They are very well adapted beings, which appeared on Earth practically together with mammals. This is one of the reasons why they are still so difficult to fight, ”says Marcelo Santos da Silva, a researcher at the Botucatu Biosciences Institute, at Universidade Estadual Paulista (IBB-Unesp).
Silva coordinates a project financed by Fapesp in the Young Researcher modality that studies a specialized group of molecules present in these parasites.
The work seeks to understand their role in the life cycle of trypanosomatids, in order to verify the possibility of being explored in the future as targets for drugs.
“Facing neglected tropical diseases is a major challenge, which will not be solved by a single organization. Uniting committed scientists from around the world is the path to success and I commend Fapesp for this approach. Partnerships such as that of DNDi with the Foundation help to raise awareness of the need for research and development for these diseases, discover new drugs and help train more young researchers, who will continue this work throughout their careers ”, concludes Mowbray, from DNDi .