Scientists at Brazil’s National Energy and Materials Research Center are analyzing the antiviral action of commercially available drugs in cultured cells (image: active compound from commercially available drug (light blue) interacting with key protein in life cycle of novel coronavirus (purple) / LNBio)

Published on 03/25/2021

By André Julião  |  Agência FAPESP – A group of researchers in Brazil are seeking a new treatment for COVID-19, the disease caused by the novel coronavirus SARS-CoV-2, based on a strategy known as drug repurposing, which consists of testing the action of existing licensed drugs against different diseases from those for which they were originally developed. 

The researchers are affiliated with the National Bioscience Laboratory (LNBio) at the National Energy and Materials Research Center (CNPEM) in Campinas, state of São Paulo. 

They have initially selected five drugs that target one of the virus’s proteases, enzymes that play a key role in its life cycle. Later they will test four other drugs against molecular targets with different functions in SARS-CoV-2.

The group are part of a network established by the Ministry of Science, Technology, Innovation and Communications (MCTIC) to organize research on the coronavirus at laboratories throughout Brazil with the goal of finding solutions to the pandemic. Some of the researchers involved are conducting projects funded by FAPESP.

“In this network, called RedeVírus MCTIC, each participating group has a mission. Ours is drug repurposing. As soon as we have results, they’ll immediately be sent to another group, who will conduct trials in patients,” said Daniela Barretto Barbosa Trivella, scientific coordinator of LNBio and one of the researchers involved in the study.

“The protease we’re targeting is responsible for a process that activates the virus, enabling it to infect cells and multiply,” Trivella explained. She is the principal investigator for a project funded by FAPESP and conducted in collaboration with the University of Nottingham in the United Kingdom to elucidate the functioning of cellular receptors considered potential therapeutic targets.

“A new drug can take as long as 15 years to come to market. That’s why we chose this strategy as the best option in the short run. The idea is to use drugs licensed for other diseases to combat the coronavirus. An example is a hydroxychloroquine, which is indicated for malaria but used experimentally to treat patients with COVID-19,” said Eduardo Pagani, Head of Innovation at LNBio.

The advantage of this strategy, he added, is that if drugs with the potential to treat COVID-19 are found, their efficacy in combating the disease can be tested directly in patients, since regulators like ANVISA, Brazil’s national public health surveillance authority, already hold all the requisite information on the safety of these drugs, which were tested in humans before coming to market.

The researchers stress, however, that although these drugs are available from pharmacies none of them has been tested in patients with COVID-19. Clinical trials are therefore mandatory to assure their safety and efficacy in treating this disease.

Five candidates

The group found the first five candidate drugs for use against SARS-CoV-2 by using computer simulations to screen 2,000 drugs approved to treat other diseases by the United States Food and Drug Administration (FDA).

“We ran simulations for over a month in a high-performance computer system. The molecule had to fit into what’s known as the catalytic site of the protease and remain there after movement of the molecules was simulated. Those that remained connected stayed in the protocol. The others were discarded,” said Paulo Sergio Lopes de Oliveira, a researcher at LNBio responsible for the computation part of the research.

Oliveira is the principal investigator for the project “Detection and characterization of protein cavities using parallel computing and molecular descriptors” funded by FAPESP.

In addition to resources for the ongoing project, his team used computers purchased with a multiuser equipment grant, for which the principal investigator was Wilson Araújo da Silva Junior, a professor in the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP).

The simulations resulted in the identification of 16 drugs with the potential for use in combating SARS-CoV-2. Five of these were selected for testing in cells infected with the coronavirus. Availability on the Brazilian market at a relatively low cost was one of the selection criteria.

Biosafety

Testing of the drugs’ action against infected cells is led by Rafael Elias Marques Pereira Silva, a researcher at LNBio and principal investigator for two projects funded by FAPESP, on the therapeutic potential of chemokines, and on the biology of viral diseases. 

The tests are performed at the Laboratory for Research on Emerging Viruses (LEVE) in the University of Campinas’s Biology Institute (IB-UNICAMP). LEVE is led by José Luiz Proença Módena, a professor at IB-UNICAMP and principal investigator for the project “Pathogenesis and neurovirulence of emerging viruses in Brazil”, which is also funded by FAPESP. LEVE is certified for Biosafety Level III (BSL-3), the next-to-highest level of biosafety.

“In light of the stringent biosafety requirements, the tests are very exhaustive and practically have to be performed one by one. This makes prior selection of drugs especially important,” Trivella said.

Marcio Chaim Bajgelman, head of LNBio’s Viral Vector Laboratory (LVV), is also participating in the study. Bajgelman’s research interests include the development of drug trials involving the use of biological nanoparticles to deliver molecules to human cells. He is the principal investigator for a project supported by FAPESP.

The researchers are currently preparing to test four more molecular targets present in the virus. The bioassays will be conducted by Artur Torres Cordeiro, also a researcher at LNBio, under the aegis of a project funded by FAPESP.

Simulations with the 2,000 existing drugs will be run for each of the new targets. The researchers expect to identify 60 candidate drugs for in vitro testing with isolated targets and the virus. Between one and three will be selected for clinical trials.

Finding more than one drug is strategic to ensure that the virus does not develop drug resistance. In antiviral treatments for HIV, for example, different combinations of drugs are used to attack different molecular targets of the virus.

“The drugs identified in this research undertaking could be combined with each other or even with hydroxychloroquine, for example, to increase the chances of a cure,” Pagani said.

Testing of the first five candidate drugs has already begun. The results are expected in about three weeks.

 

Source: https://agencia.fapesp.br/32909