Jose Tadeu Arantes | Agencia FAPESP – a new compound that prevents replication hepatitis C (HCV) at different stages of the cycle – and is capable of acting on bacteria, fungi and cancer cells – researchers at Unesp have synthesized.
Study – supported by FAPESP through several research promotion tools [veja a relação adiante] – is described in an article published in the journal Scientific Reports of Nature.
"What we did is combining the existing molecules, through laboratory synthesis, in order to produce new compounds with biological potential.This method is called bioconjugation.To bioconjugation we synthesized six compounds and tested them on HCV genotypes 2a and 3a.We managed to come to compounds with great therapeutic potential, "said Paulo Ricardo da Silva Sanches, one of the two main authors of the Agencia FAPESP study.
The hepatitis C virus represents a significant genomic variability, showing at least six major genotypes, each of which has subtypes. Genotypes 2a and 3a are the most common subcipients of circulating HCV. Compound capable of destroying them – AG-hexate – synthesized from gallic acid and hepatic peptide.
"We found that this compound works in almost every phase of the HCV replication cycle – which is not a common antiviral feature. They usually have individual, isolated targets such as capsid proteins, membrane receptors or specific proteins such as NS3, inhibiting specific processes such as the introduction of viruses into cells, the synthesis of genetic and protein material, the conclusion and release of new viral particles. AG-hecat, on the other hand, presented broad activity, acting in several stages of the cycle, explained Sanches.
"The compound also has activity in the so-called" Lipid droplets "- lipid droplets in which the virus circulates in cells and protects it from enzyme attacks. AG-hecat reduces these lipid droplets and leaves the replicative complex of the virus that is exposed to the cellular enzyme," he continued.
The researchers tested AG-hecat in the whole source and so-called "subgenomic replicons", which have all the elements to replicate the genetic virus of the virus in the cells, but are unable to synthesize the proteins responsible for the infection. And the compound was effective in all tests.
The second virtue presented by the compound was a high selectivity index. This means that the virus attacks much more than the host cell. And therefore it has the potential to be used as a cure for the treatment of the disease.
"Although the compound exhibits low activity in red blood cells, the molecule needs to make changes in its structure in order to further reduce toxicity, which is what we are doing now, so research can evolve from in vitro phase to in vivo phase," he said. UNESP researcher.
As Professor Eduardo Maffud Cilli, Doctor Counselor of Sanches at the Unesp Chemistry Institute in Araracara (SP) reported, "the average time for the planning and development of therapeutic peptides is 10. It has just come out with a study with this data. spent on the development of the AG-hexate molecule. "" Given the statistical average, it takes another eight years before the drug reaches the market. "
Cilli took part in the study and signed an article published in scientific reports. "The great news is that this molecule does not only work on HCV, it can also behave on bacteria, fungi and cancer cells. In addition, since the zick and yellow fever have very similar replication cycles for HCV, we will also test the effectiveness of AG-hepatitis in relation to these viruses, "he said.
In the case of cancer, the molecule interacts and destroys the affected cell's membrane. Here, the selectivity of the AG-hexate action is caused by the fact that the cell-modified cell has a greater amount of negative effects on the surface than the normal cell. And the peptide has a positive charge. Then, the action is electrostatic attraction. In the case of a virus, the mechanism of action of the molecule is more complex, as shown in the illustration.
Studies were conducted at the Laboratory for Synthesis and Biomolecular Studies at the UNESP Institute of Chemistry in Araracara, co-ordinated by Professor Eduard Maffouh Cilli and the Laboratory for Genomic Studies of the UNESP Institute for Bioscience, Letters and Correct Sciences in Sao Jose do Rio Preto, coordinates Professor Paula Rahal, Doctor of Science, Mariano Nogueira Batista, a researcher who shares the authorship of this work with Sanches.
In addition to Sanches and Cilla, they participated in the studio of Marianne Nogueira Batista, Bruno Moreira Carneiro, Ana Claudia Silva Braga, Guilherme Rodrigues Fernandes Campos and Paula Rahal.
The research was supported by FAPESP within the Center for Innovation in Biodiversity and Drugs (CIBFar), one of the Centers for Research, Innovation and Enlargement (CEPID) funded by FAPESP. The Foundation also awarded scholarships for the following projects:
"Development of multifunctional drugs for combined hepatocellular carcinoma and HCV therapy".
"Evaluation of synthetic peptides in order to inhibit hepatitis C virus".
"Adaptation of Hepacivirus with rodent from HCV to muscle host"
Article GA-Hecate antivirus properties throughout the HCV cycle represent a new antivirus class and open the door for the development of a wide-range antivirus, you can read at vvv.nature.com / articles / s41598-018-32176-v.