Researchers from USP (University of São Paulo) synthesized a peptide – molecules composed of amino acids linked together – inspired by the natural receptor of the SARS-CoV-2 virus, the coronavirus, in human cells, the ACE2 protein. The molecule was shown to be capable of protecting human lung cells from infection in tests in vitro. Additionally, it treated inflammation caused by the virus in mice susceptible to COVID-19.
These results were published in magazine Antiviral Research. They indicate a possible path for the creation of more effective antiviral blocker-type drugs against the disease, which has already killed more than 700,000 Brazilians.
According to the authors in the article, the SARS-CoV-2 virus connects its protein spike (S) to the ACE2 protein located on the surface of human cells to invade them.
“The moment of infection happens as if it were the fit between a key and a lock”, compares Geraldo Aleixo Passosprofessor of the department of basic and oral biology at the School of Dentistry of Ribeirão Preto at USP, and one of the coordinators of the research. “The ‘key’ represents the spike protein of the virus, and the lock, the ACE2 receptor of human cells. The ‘teeth’ of the key, that is, the amino acid residues of the spike, are complementary to the ‘secret lock’, the amino acids of ACE2.” The amino acid residues of the spike and ACE2 interact with each other and this “open the door” for the virus to infect human cells.
The better this interaction, the greater the virus’s potential for infection – this is, in fact, the factor that made the B.1.1.7 variant of SARS-CoV-2 so much more contagious, as shown by a article from the same group of researchers published in 2021 on the platform bioRxiv.
In the new study funded by Fapesp (São Paulo Research Foundation), projects 17/10780-4and 19/02418-9scientists investigated ways to block the binding of spike with ACE2 and, consequently, protect human cells from infection. To do this, they designed a mimetic peptide (similar) to the ACE2 receptor using protein bioinformatics programs and tested modifications to its amino acid residues – in the analogy made by Passos, the scientists changed the “lock secret”.
During this process, they discovered that some specific parts of the ACE2 receptor – more specifically the amino acid residues F28, K31, F32, F40 and Y41 present in the alpha helix α1, one of the secondary structures of this protein – are crucial in this interaction.
Experiments in vitro using human lung cells in culture and in vivo with mice susceptible to the virus confirmed that the synthetic peptide was able not only to control the infection, but also to treat animals that had been previously infected, causing the lung inflammation caused by covid to decrease drastically.
“We managed to ‘trick’ the virus by giving it a free part of the ACE2 receptor [o peptídeo sintético]which, interacting with the spike before this protein binds to the cell surface, obstructs its entry. By studying the structural basis of the recognition of the ACE2 receptor by SARS-CoV-2, we have developed a molecular barrier against the virus”, explains Passos.
Treatment for immunosuppressed individuals
“Covid-19 was controlled with mass vaccination, which drastically reduced the number of cases and deaths, and is therefore the best option to prevent the disease from spreading among populations. However, the SARS-CoV-2 virus is still in circulation, infecting thousands of people around the world. In addition, the circulating virus can undergo new mutations. Studies on its evolution indicate that the prospect of new epidemics or even a pandemic, such as that caused by the original Wuhan strain and subsequent lineages, is plausible, and precisely for this reason, we scientists need to continue investigating the subject.”, declares Passos.
According to the researcher, a product like the peptide identified in this study, which does not depend on the immune system to act, could be designed specifically for each new variant. Since it acts quickly, by functioning as a molecular shield, it could be effective in blocking the virus in the short term, especially in immunosuppressed patients or children with immunodeficiencies and low immune response to vaccines.
The study was multidisciplinary and multicenter, bringing together researchers from the Center for Research in Virology, Crid (Center for Research in Inflammatory Diseases) and the Genetics Department of the Ribeirão Preto School of Medicine, USP, in addition to the CTI (Renato Archer Information Technology Center), linked to Ministry of Science, Technology and Innovation. It was financed by CNPq (National Council for Scientific and Technological Development) and the Capes (Coordination for the Improvement of Higher Education Personnel).
With information from FAPESP Agency.
Report by Julia Moióli.
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