José Tadeu Arantes | Agência FAPESP is a new compound that inhibits cellular replication Hepatitis C (HCV) at different stages of its cycle – and capable of acting on bacteria, fungi and cancer cells – were synthesized by researchers at UNESP.
A study sponsored by FAPESP with several research promotion tools [veja a relação adiante] – was described in an article published in the journal "Scientific reports group" Nature.
"What we did was combine existing molecules using laboratory synthesis to create new compounds with biological potential. This method is called bioconjugation. Using bioconjugation, we synthesized six compounds and tested them for HCV genotypes 2a and 3a and we managed to achieve connection with great therapeutic potential, "said chemist Paulo Ricardo da Silva Sanches, one of two major authors of the study, Agência FAPESP.
Hepatitis C virus has a significant genetic variability and has at least six main genotypes, each with subtypes. Genotypes 2a and 3a are the most commonly used circulating HCV subtypes. The compound that can destroy them, AG-hecate, was synthesized from gallic acid and hecate peptide.
"We found that this compound operates in almost all stages of the HCV replication cycle, which is not a common feature of antiviral drugs. They typically contain isolated, isolated targets, such as kapidide proteins, membrane receptors, or specific proteins such as NS3, which inhibit specific processes such as , virus penetration in cells, genetic and protein synthesis, new particle collection and release of viral infections. On the other hand, AG-hecate explained to Sanches that it extensively works in several stages of the cycle.
"This compound also has activity in the so-called" lipid colonies "- lipid droplets in which the virus circulates in the cells and protects them from the enzyme attack. AG-hecate breaks down these lipid drops and leaves the virus-replicating complex that is exposed to cellular enzymes," he continued.
The researchers tested AG-hecate for both the whole virus and the so-called "subgenomic replicon," which has all the elements to replicate the viral genetic material in cells, but is unable to synthesize the proteins responsible for the infection. And the connection was effective in all tests.
Another feature of the connection was its high selectivity index. This means that the virus is attacking far more than the host. It can therefore be used as a medicine in the treatment of the disease.
"Although the compound causes a small activity in the case of red blood cells, the molecule needs to change its structure to further reduce its toxicity, which is what we are working on so that the research can develop from the in vitro phase to the in vivo phase," said UNESP researcher.
As reported by prof. Eduardo Maffud Cilli, Ph.D. in Sanches, Institute of Chemistry at the Institute of Chemistry at Arasarvar (SP), Institute of Chemistry, Sanches, "The average time for the planning and development of therapeutic peptides is 10 years. A study with these data has just come out." For now, about two years have been spent on the development of the AG-hecate molecule. " "Given the statistical average, it will take eight years before the product comes onto the market."
Cilli participated in the study and also signed the article published in the scientific reports. "The great news is that this molecule not only works on HCV, it can also affect bacteria, fungi and cancer cells. In addition, since zico and yellow fever viruses are very similar to reproductive cycles against HCV, we will also check the effectiveness of AG-hecate in relation to with these viruses, "he said.
In the case of cancer, the molecule interacts and destroys the affected cell membrane. In this case, the selectivity of AG-hecate activity is due to the fact that cancer-modified cells have a higher level of negative charge on the surface than the normal cell. And the peptide has a positive charge level. Then the activity is related to electrostatic attraction. In the case of a virus, the molecular mechanism of action is more complex, as shown in the figure.
Studies were conducted at the UNESP Institute of Chemistry, Institute for Synthesis and Biomolecular Research in Araracar, coordinated by Professor Eduardo Maffaud Cilli and the Institute of Biomedicine Genomics Research Laboratory, UNESP Letters and Precision Sciences São José do Rio Preto, coordinated by Professor Paula Rahal, Mariana Nogueira Batista Doctor, Researcher , which is shared by the author of this work with Sanches.
In addition to Sanches and Cilli, they participated in the study of Mariana Nogueira Batista, Bruno Moreira Carneiro, Ana Cláudia Silva Braga, Guilherme Rodrigues Fernandes Campos and Paula Rahal.
The FAPESP study was supported by the Center for Biological Diversity and Drug Innovation (CIBFar), one of the FAPESP-funded Research, Innovation and Distribution Centers (CEPIDs). The Foundation has also awarded scholarships for the following projects:
"Multifunctional pro-drug development for combined hepatocellular carcinoma and HCV therapy."
"Evaluation of synthetic peptides by targeted inhibition of hepatitis C virus".
"Adapting the Hepatic Virus to the Mouse Hcv Associated with the Rat-Derived Rodent"
The full cycle of anti-viral HCV anti-influenza virus displays a new antiviral class and opens the door for developing a wide range of antiviral medicines, readable at www.nature.com/articles/s41598-018-32176-w.