Consortia seek new drugs for neglected diseases

Research institutions in Brazil and worldwide are networking with pharmaceutical companies to reduce the time required to develop new treatments for Chagas and malaria, among other diseases.

By Elton Alisson

Agência FAPESP – Pharmaceutical companies are increasing their participation in the development of new drugs and new formulations of existing products for the treatment of neglected diseases such as malaria, dengue fever and Chagas disease.

One of the main reasons for this, according to experts, is the activities of consortia, which are networks coordinated by international not-for-profit research and development organizations such as the Drugs for Neglected Diseases Initiative (DNDi) and Medicines for Malaria Ventures (MMV).

Both organizations fund the most costly stages of drug development, which include molecule discovery, preclinical assays, and toxicity testing, performed by universities and research institutions in different countries, including Brazil.

Pharmaceutical companies can join in during the clinical trial and large-scale production stages, reducing the time required to develop new treatments for diseases that are common in developing countries.

“The R&D process for a new drug can take as long as 15 years,” said Luiz Carlos Dias, a professor at the University of Campinas’s Chemistry Institute (IQ-UNICAMP) in São Paulo State, Brazil, in a panel session on health during FAPESP Week Buenos Aires, held from April 7 to 10 in the capital of Argentina by FAPESP in partnership with Argentina’s National Scientific & Technological Research Council (CONICET).

“One of the objectives of international organizations such as the DNDi and MMV is to cut the time needed to develop new treatments for neglected diseases to seven or eight years,” said Dias, who heads UNICAMP’s Synthetic Organic Chemistry Laboratory.

Approximately two years ago, the lab began partnering with the DNDi and MMV, which are based in Geneva, Switzerland and funded by institutions such as the Bill & Melinda Gates Foundation, Doctors Without Borders (MSF) and the Wellcome Trust.

The DNDi, launched in 2003, is working to develop between 11 and 13 new treatments for leishmaniasis, malaria, pediatric HIV, sleeping sickness and Chagas disease, among other diseases, by 2022.

Through partnerships with universities, research institutions and pharmaceutical companies, the DNDi has already delivered five new treatments for malaria, sleeping sickness and visceral leishmaniasis. These treatments are currently used in Latin American, African and Asian countries.

In addition, Dias said that the DNDi partnered with Pernambuco State Pharmaceutical Laboratory (LAFEPE) and Argentina’s Fundación Mundo Sano and Ministry of Health to develop a new pediatric dosage form of benznidazole, which is the main drug used to treat Chagas disease.

“In Latin America, Chagas disease kills more than any other parasite-borne disease including malaria,” Dias said, “and the DNDi reckons that fewer than 1% of infected people are currently receiving treatment. New alternative treatments must be developed for the disease.”

New compounds

According to Dias, benznidazole was developed more than 40 years ago and is the only drug presently available to treat Chagas disease.

Although it is extremely powerful, the drug has side effects that may cause adverse reactions in patients, who often stop taking it as soon as they feel the first signs of improvement.

“Discontinuing the drug is bad for the treatment of any parasite-borne disease because the parasite acquires resistance,” Dias said.

To search for an alternative compound to benznidazole, the DNDi has established an innovative research consortium called Lead Optimization Latin America (LOLA). This is the first time a drug discovery program has been set up in a region where Chagas disease is endemic.

The Brazilian members of the consortium include Dias’s lab at UNICAMP and the Medicinal Chemistry Laboratory at the University of São Paulo’s São Carlos Institute of Physics (IFSC-USP), in collaboration with the lab’s senior researchers Adriano Andricopulo and Glaucius Oliva.

The consortium’s other members are Belgium’s University of Antwerp, the Swiss Tropical & Public Health Institute, Scotland’s University of Dundee, the London School of Hygiene & Tropical Medicine, GlaxoSmithKline (GSK), AbbVie (formerly Abbott), Pfizer, and China’s Wuxi AppTec.

“The goal is to identify a compound that is more effective than benznidazole, is simultaneously active against drug-resistant strains, non-toxic, non-teratogenic [does not cause fetal abnormalities] and non-genotoxic [not harmful to DNA], is usable by children and pregnant women, and is chemically stable in places with temperatures ranging from 30°C-35°C. That’s a major challenge,” Dias said.

His lab’s participation in LOLA focuses on the chemical synthesis of potential compounds identified by the DNDi.

The international organization receives libraries of compounds that are tested in medicinal chemistry labs in various parts of the world from large pharmaceutical companies. If it identifies a lead, i.e., a potential molecule for the treatment of Chagas or another neglected disease, the DNDi sends it to labs such as Dias’s. The researchers at UNICAMP are responsible for chemically synthesizing such compounds using simple, commercially accessible substances and for preparing structural analogues by means of chemically modifying the molecules.

They are supported by the DNDi’s medicinal chemists, including Simon Campbell, the British researcher who led the group that discovered Viagra.

“Campbell and other researchers at the DNDi help us with the chemical modifications that must be made to optimize the effectiveness of each molecule” Dias said. The molecules and structural analogues prepared by UNICAMP’s research group are then sent to IFSC-USP’s Medicinal Chemistry Laboratory, the University of Antwerp’s Microbiology, Parasitology & Hygiene Laboratory and the Swiss Tropical & Public Health Institute for primary and secondary parasitology studies.

The leads are also sent to the University of Dundee and to GSK to be submitted to biological tests that serve as guidance for the structural modifications made by the UNICAMP group.

In addition, some leads are sent to AbbVie and Pfizer for absorption, distribution, metabolism and excretion studies.

The compounds approved in this series of studies are formulated by Wuxi AppTec. After this stage, they are tested in vivo in mice at the London School of Hygiene & Tropical Medicine and IFSC-USP’s Medicinal Chemistry Laboratory.

“The aim is to optimize the properties of the molecules so that they display activities similar to those of a drug,” Dias said.

Promising molecules

In their work with the LOLA consortium, the researchers have already identified molecules that are extremely powerful against Trypanosoma cruzi, the parasite that causes Chagas disease.

A major challenge, however, is how to increase their solubility.

“We have molecules that kill the parasite very efficiently but that are not sufficiently soluble, and when we succeed in improving the solubility of these molecules, their activity diminishes,” Dias said.

The same researchers are also collaborating with the MMV under the aegis of a program called Brazil Heterocycles, for which they have synthesized two promising molecules for treating malaria. One is active against eight drug-resistant strains of the malaria parasite.

Other collaborators with the program are affiliated with Imperial College London, Monash University in Australia, GSK in Spain, AstraZeneca in the UK, and Syngene in India.

According to Dias, the program aims to develop more powerful compounds against malaria that can be combined with artemisinin.

Although artemisinin is the most powerful compound used against malaria today, it also presents the problem of parasite resistance.

“Artemisinin doesn’t completely kill the parasite, so it must be combined with another compound to achieve total inhibition of the parasite in all of its life stages,” Dias said.