The genetic information of SARS-CoV-2 has been successfully destroyed by a research team led by the Technical University of Munich (TUM) using specialized enzymes after the virus has penetrated the cell. The findings could be used to develop a treatment for COVID-19.
Viral RNA can be destroyed by a special mechanism called RNA-Interference. Image Credit: iStockphoto.com/koto_feja
The building blueprints for proteins and other compounds are found in human DNA. However, for the cell to manufacture them, it must first create a transcript of these building instructions, which takes the form of so-called RNA molecules. The cells recognize the transcript and put it into action.
Dr Thomas Michler, who led the current study at the Institute of Virology of TUM and Helmholtz Zentrum München explains, “However, there is also a mechanism that can very specifically destroy this RNA, which takes place in all human cells as part of gene regulation. It is the so-called RNA interference.”
Short bits of RNA called siRNA are generated in the cell during this process (small interfering RNA). These segments can bind to particular locations on an RNA molecule. The RNA-Induced Silencing Complex (RISC) is formed when siRNA and proteins combine to generate an enzyme that breaks the target RNA.
Virus introduces RNA into cell
Efforts have been made for quite some time now to make therapeutic use of this mechanism. A lot of progress has been made in this area over the last few years. Among other things, it is now possible to stabilize siRNA by chemical modifications so that it is not broken down so quickly in cells.”
Ulrike Protzer, Head, Institute of Virology, Technical University of Munich
There are two RNA interference targets in SARS-CoV-2. First, the virus’s genome is made up of RNA, which is delivered into the infected cell and serves as the model for new viruses. Second, subgenomic RNA molecules are produced, instructing the host cell to generate viral proteins.
Start of the replication cycle as the most effective point of attack
The study team was largely interested in determining which of the virus’s RNA structures may be targeted and at what point in the replication cycle therapy should occur.
Our main finding is that the RNA interference is most effective when the virus has just penetrated into the cell.”
Shubhankar Ambike, Study First Author, Technical University of Munich
In this study, siRNAs that target the viral genome specifically outperformed siRNAs that target subgenomic RNA molecules.
The researchers also conducted tests on human lung tissue infected with SARS-CoV-2, in collaboration with colleagues from Ludwig Maximilian University of Munich and the German Research Center for Environmental Health Helmholtz Zentrum München. The experiments backed up their findings.
The researchers are now working on a follow-up effort to develop a means for delivering the active ingredient to the lungs in the most efficient way feasible. The findings could subsequently be used to develop treatments for other viral respiratory infections.
Ambike, S., et al. (2022) Targeting genomic SARS-CoV-2 RNA with siRNAs allows efficient inhibition of viral replication and spread. Nucleic Acids Research. doi.org/10.1093/nar/gkab1248.