Fiocruz studies antiviral drug against Covid-19

The Oswaldo Cruz Foundation (Fiocruz) is developing an oral antiviral against Covid-19 in partnership with the company Microbiológica and the Center for Innovation and Pre-Clinical Tests (CIEnP).

The substance, named MB-905 by the researchers, was purified from a plant hormone called kinetin. The compound proved to be effective in inhibiting the replication of the coronavirus in human liver and lung cell lines, in addition to helping to curb the inflammatory process triggered by the virus.

The research results were published in the journal Nature Communication. According to Fiocruz, the pre-clinical dossier was forwarded to the National Health Surveillance Agency (Anvisa). After approval by the agency, the first phase of clinical trials should begin.

“The idea is that we can then fulfill all the necessary steps for the development of this drug in Brazil, from the planning phase, synthesis, chemical characterization, characterization of the mechanism of action and the pre-clinical studies of safety, tolerability and efficacy . Our goal is for this substance to become an innovative antiviral, developed in Brazil since its conception, with a view to giving us more independence in this type of technology, which would have a high import cost for the country. [Sistema Único de Saúde] SUS”, explained researcher Thiago Moreno, from the Center for Technological Development in Health (CDTS/Fiocruz), one of the main authors of the study, in a statement.

How the antiviral under development works

MB-905 disorganizes the virus genome and causes a kind of catastrophe in the synthesis of its genetic material (RNA), a crucial process for viral replication.

The RNA molecule is composed of four bases that need to be linked in a certain way (A with U, C with G), but the structure of kinetin is very similar to that of the A base, which allows an important enzyme of the virus, called viral RNA polymerase, incorporate kinetin in place of base A.

Kinetin, in turn, behaves randomly, sometimes as A, sometimes as G. This creates great confusion in the RNA sequence and induces the virus to make several errors during its replication process, generating many particles that are defective and they lack replicative capacity, which reduces the overall replication of the virus.

In addition to acting as an antiviral, MB-905 was also able to curb the inflammatory process triggered by the coronavirus, decreasing the levels of cytokines IL-6 and TNFα in infected monocytes.

According to Moreno, the mechanism is essential to combat Covid-19, since the disease not only manifests viral destruction, but often serves as a trigger for an exacerbated inflammatory response in the body.

“We adjusted our substance identification process based on certain assumptions: the substance had to be antiviral; it needed to be antiviral in a target cell, such as cells in the respiratory tract; it needed to work as an antiviral also in cells of the immune system, which the virus manages to invade and destroy, such as monocytes; and it would need to reduce the levels of inflammatory markers associated with the viral infection”, explains the researcher.

They selected two of the main pro-inflammatory cytokines to use as indicators, IL-6 and TNFα. Based on that, they carried out a screening already oriented to look for substances that could be both antiviral and capable of reducing this inflammatory insult produced by the virus.

“What I mean is that I’m not looking for an antiviral alone. Like dexamethasone, like aspirin, this product cannot reduce any type of inflammation, but only selective inflammation induced by the virus. We also understand that this can potentially help this substance to have a slightly broader therapeutic window, perhaps by managing to reduce both the antiviral phase and the inflammatory phase associated with the virus,” he said.

Other results

For researchers, Covid-19, as well as other diseases of a viral nature, will not be cured with a single drug. They claim that it will be necessary to administer a set of drugs to treat the most severe cases of the disease and those at higher risk, such as patients with comorbidities.

Based on MB-905’s mechanism of action, the group investigated which substances could potentiate the effect of kinetin. The study also identifies advantages of MB-905 over other substances whose clinical benefit has been demonstrated in independent clinical trials.

Remdesivir, for example, is injectable, while kinetin will be administered as a pill, allowing the patient to receive the drug as early as possible. In relation to molnupiravir, MB-905 obtained better results in safety tests. As it disorganizes the viral genome without interfering with the cell, kinetin was considered safe according to the Ames test.