José Tadeu Arantes | Agência FAPESP – With new compounds, Hepatitis C (HCV) has been synthesized by Unesp researchers at several stages of the cycle – which can act on bacteria, fungi, and cancer cells.
Research – Supported by FAPESP through several tools to facilitate research [veja a relação adiante] – Described in an article in the Scientific Reports journal of the group Nature.
"What we did was to combine the existing molecules with laboratory synthesis to produce new compounds with biological potential." This method is called bioadhesion. By bioconjugation, we synthesize six compounds and generate HCV genotypes 2a And 3a, and we were able to reach compounds with great therapeutic potential, "said Paulo Ricardo da Silva Sanches, one of the two leading authors of this study, to Agência FAPESP.
Hepatitis C viruses exhibit significant genomic diversity representing at least six major genotypes, each with subtypes. Genotypes 2a and 3a are the most common subtypes of circulating HCV. A compound capable of degrading galactic acid and hecate peptide (AG hecate) was synthesized.
"We have found that this compound works at almost every stage of the HCV replication cycle, which is not a common feature of antiviral drugs, they are usually single, isolated, such as capsid proteins, membrane receptors, or specific proteins such as NS3 It has targets and inhibits certain processes such as virus entry into cells, synthesis of genetic and protein substances, assembly and release of new particles, viral infections. Meanwhile, AG hecate did.
"This compound has the activity of the lipid droplets that the virus circulates in the cell and protects it from attack by the enzyme AG-hecate depletes water droplets from these lipids, Leave the replication complex of.
The researchers tested AG-hecate in whole viruses and so-called "subgenomic replicons", which have all the elements for replication of viral genetic material in cells but can not synthesize proteins responsible for infection . And this compound was efficient in all tests.
Another virtue presented by the compounds was a high selectivity index. This means that the virus attacks far more than the host cell. Therefore, there is a possibility of being used as a drug in the treatment of diseases.
"The compound is almost inactive in red blood cells, but the molecule has to change its structure to further reduce its toxicity, which is what we are currently studying, so research can evolve from in vitro to in vivo," says Unesp. .
"The average time for planning and development of therapeutic peptides is 10 years," said Dr. Eduardo Maffud Cilli, an advisor to Dr. Sanches of the Unesp Chemical Institute in Araraquara (SP). It was used to develop AG-hecate molecules. "" With statistical averages taken, it will take about eight years before drugs are put on the market, "he added.
Cilli participated in this study and also signed a paper published in Scientific Reports. "The good news is that this molecule does not work on HCV, it can act on bacteria, fungi and cancer cells, and because zika and yellow fever virus have replication cycles very similar to HCV, the effect of AG- I will test it, "he said.
In the case of cancer, the molecule interacts with and destroys the membrane of the affected cells. Here, the selectivity of the AG-hate action is due to the fact that cancer-modified cells have a greater positive charge on their surface than normal cells. And the peptide is positively charged. Then, the action is by electrostatic attraction. In the case of viruses, the mechanism of action of molecules is more complex, as shown in the figure.
This work was carried out at the Unesp Biosciences, Letters and Exact Sciences genomics laboratories at Synthetic and Biomolecular laboratories at Unesp Institute in Araraquara, Professor Eduardo Maffud Cilli and at São José do Rio. Preto is the author of the study by Sanli Professor Paula Rahal, Ph.D., of Mariana Nogueira Batista, a divisional researcher.
In addition to Sanches and Cilli, they participated in Mariana Nogueira Batista, Bruno Moreira Carneiro, Ana Cláudia Silva Braga, Guilherme Rodrigues Fernandes Campos and Paula Rahal.
The study was supported by FAPESP within the scope of the Center for Biodiversity and Drug Innovation (CIBFar), one of the research, innovation and dissemination centers (CEPIDs) supported by FAPESP. The Foundation also awarded a fellowship to the following projects.
& Quot; Development of multifunctional pro-drugs for combination therapy for hepatocellular carcinoma and HCV & quot;
& Quot; Evaluation of synthetic peptides in target inhibition of hepatitis C virus & quot ;.
& Quot; Adaptation of hepatitis viruses derived from mouse-derived rats to Hcv-related rats & quot;
The GA-Hecate antiviral nature of the HCV cycle represents a new antiviral agent and opens the door for the development of a broad range of antiviral agents (www.nature.com/articles/s41598-018-32176-w).