José Tadeu Arantes | Agência FAPESP – a new compound that inhibits replication hepatitis C (HCV) at different stages of its cycle – and is able to work on bacteria, fungi and cancer cells – have been synthesized by researchers at Unesp.
A study supported by FAPESP with several instruments to promote research [veja a relação adiante] – has been described in an article published in the Scientific Reports of Nature magazine.
"What we have done is to combine existing molecules with the help of a laboratory synthesis for the production of new compounds with biological potential, which is called bioconjugation. Six compounds were synthesized by bioconjugation and tested on HCV genotypes 2a and 3a. we have reached a compound with a high therapeutic potential, "said Paul Ricardo da Silva Sanches, a chemist, one of the two main authors of the Agência FAPESP study.
The hepatitis C virus represents an important genomic variability that has at least six major genotypes, each having a subtype. Genotypes 2a and 3a are the most common subtypes of circulating HCV. The compound that could be destroyed – AG-hexate – was synthesized from gallic acid and peptide hepta.
"We found that this compound works at almost every stage of the HCV replication cycle – which is not a common feature of antiviral drugs. They usually have single, isolated targets such as capsid proteins, membrane receptors or specific proteins such as NS3 that inhibit specific procedures , such as the introduction of a virus into cells, the synthesis of genetic and protein material, the assembly and release of new viral contaminant particles. AG-hecat, on the other hand, has introduced a broad activity that operates in several phases of the cycle, Sanches explained.
"The compound also has activity in so-called lipid droplets – droplets of lipids inside which the virus circulates in cells and protects it against the attack of enzymes. AG-hecate empties these drops of lipids and leaves the replicative complex of the virus exposed to cell enzyme activity," he continued.
The researchers tested AG-hecat in the whole source and the so-called "subgenomic replicons", which have all the elements for replicating viral genetic material in cells, but can not synthesize the proteins that are responsible for the infection. And the compound was effective in all tests.
The second virtue presented by the compound was its high selective index. This means that the virus attacks much more than the host cell. And therefore it has the potential to be used as a medicine in the treatment of the disease.
"Although the compound shows a small activity in red blood cells, the molecule must change in its structure to further reduce its toxicity. In this work, we are now working to investigate the development of the in vitro phase into the in vivo phase," said the researcher Unesp.
According to Professor Eduardo Maffud Cilli, Doctoral Consultant at Sanches at the Unesp Chemistry Institute in Araraquara (SP), "the average time for the design and development of therapeutic peptides is ten years." A study of this data has just come out. has been spent for about two years. "" Depending on the statistical average, it will take another eight years for the drug to reach the market. "
Cilli participated 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 work on bacteria, fungi, and cancer cells. In addition, because zirconium viruses and yellow fever have very similar repetitive cycles for HCV, we will also test the effectiveness of AG-hepatitis according to these viruses, "he said.
In the case of cancer, the molecule interacts and destroys the affected cell's membrane. Here the selectivity of AG-hecate is due to the fact that a cell that is modified in cancer has a larger amount of negative charges on the surface than a normal cell. And the peptide has a positive charge. Then there is electrostatic attraction action. In the case of a virus, the mechanism of action of the molecule is more complex than shown in the figure.
Studies were conducted at the Laboratory for Synthesis and Biomolecular Studies of the UNESP Chemical Institute in Ararquara, coordinated by Professor Eduardo Maffud Cilli and the Laboratory for Genomic Studies of the Institute of Biosciences, Letters and Precise Sciences of Unesp in Sao Jose do Rio Preto Head of prof. Paula Rahal, director of the doctor Mariano Nogueira Batista, a researcher who shares the authorship of this work with Sanches.
In addition to Sanches and Cilli, they also participated in a study by Mariano Nogueira Batista, Bruno Moreira Carneiro, Ana Cláudia 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 dissemination (CEPID) funded by FAPESP. The Foundation also awarded scholarships for the following projects:
"Development of multifunctional pro-drugs for combined hepatocellular carcinoma and HCV therapy."
"Evaluation of synthetic peptides in targeted hepatitis C virus inhibition".
"Adjustment of the rodent hepacivirus associated with the hcv virus on the mouse host"
The article of GA-Hecate antiviral properties throughout the entire HCV cycle represents a new antivirus class and opens the door for the development of wide-spectrum antivirals, is available at www.nature.com/articles/s41598-018-32176-w.