An article published in the journal Frontiers in cellular and infectious microbiology reports a study by researchers from the State University of Campinas (UNICAMP) and the University of São Paulo (USP) in Brazil showing how a human protein interacts with a SARS-CoV-2 protein, and describing one of the ways the virus that causes COVID-19 recruits cells to replicate.
In laboratory tests, the researchers inhibited the interaction between the molecules using a drug and thus reduced viral replication by 15 to 20%. They expect their findings to contribute to the development of treatments for COVID-19.
The human protein known as PCNA [ proliferating cell nuclear antigen ] interacts with SARS-CoV-2 M protein [ matrix ], one of the molecules that make up the membrane of the virus and give it its shape. The finding itself shows one of the ways the pathogen manipulates cellular function to drive its life cycle.”
Fernando Moreira Simabuco, professor at the School of Applied Sciences (FCA) of UNICAMP in Limeira and principal investigator of the study
The group used a range of in vitro techniques to study how the presence of the viral protein M in the body causes PCNA, a protein involved in DNA repair, to migrate from the cell nucleus, where it is normally found, to the cytoplasm, a cellular protein. region containing organelles responsible for important cellular functions.
According to the researchers, this migration shows that viral and human proteins interact, a conclusion supported by other methods, such as the use of compounds to inhibit the migration of proteins from the nucleus to the cytoplasm. In cells treated with both a compound specific for PCNA and another that inhibits the migration of different proteins, including PCNA, viral replication was reduced by 15-20% compared to untreated cells.
“If we had thought of a treatment, this reduction might not have been significant, but our main goal was to demonstrate the interaction and show that it could be a future therapeutic target,” Simabuco said.
Together with researchers from the USP School of Medicine’s Department of Pathology, they analyzed lung tissue samples obtained during autopsies of deceased COVID-19 patients (more at: agencia.FAPESP.br/32955/).
PCNA expression was found to be higher than normal in these samples, as was expression of gamaH2AX protein, a DNA damage marker, supporting the results.
“This finding may indicate another consequence of virus infection,” Simabuco said.
The first author of the article is Érika Pereira Zambalde, postdoctoral researcher at FCA-UNICAMP under the supervision of Simabuco.
Protein News
The M protein is anchored, along with the E and S proteins, in the membrane that envelops SARS-CoV-2, and is the most abundant of its four main structural proteins, called structural because they give it its shape. For this reason, it has been considered a potential target for drugs and vaccines.
S, the viral spike protein, is well known because it binds to the ACE receptor in human cells, a role that has made it the target of most current COVID-19 vaccines.
The human PCNA protein is widely studied in the context of cancer research, as evidenced by a project led by Simabuco at FCA-UNICAMP. However, little is known about the role of PCNA in viral infections.
The newly published article therefore offers a way forward for further research into this interaction between SARS-CoV-2 and PCNA, facilitating the development of therapies. A next step would be validation of the findings in animal models, although this is not yet scheduled.
Some of the experiments were carried out at the Laboratory for Studies on Emerging Viruses (LEVE) directed by José Luiz Proença Módena at the Institute of Biology (IB) of UNICAMP, with the support of FAPESP.
Research groups led by Armando Morais Ventura, professor at USP’s Institute of Biomedical Sciences (ICB), and Henrique Marques-Souza, professor at IB-UNICAMP, collaborated on the study.