Application of Gene Editing and Proteogenomics in Preventing Glycoprotein Bonding
By Diego Suchenski Loustaunau
In order to combat Covid-19, the way it infects the body must be well understood. Covid-19 is a disease caused by the virus known as SARS-CoV-2 (World Health Organization, 2020). SARS-CoV-2 binds to the human gene ACE2 using a spike glycoprotein (Walls et al., 2020). Binding of the glycoprotein to the human cell is initiated when, “the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits,” (Walls et al., 2020) which means that binding occurs between the cell’s receptors and its membrane, the S1 and S2 subunits, respectively. The furin cleavage site acts as a catalyst for the viral protein and it begins to invade target cells and weaken the immune system. In the open conformation of the glycoprotein, it binds with great affinity to the ACE2 gene, but when in the closed conformation, the binding domains of the protein do not interact with the ACE2 gene (Walls et al., 2020). When antibodies are present, the closed conformation is achieved but when they are not, the protease of the virus, the part of the virus that breaks down proteins, cleaves the membrane fusion peptide at S2 and then SARS-CoV-2 binds in its place in the open conformation and the patient develops Covid-19 (Walls et al., 2020). Without antibodies present, which can only be gained through surviving the virus or via convalescent plasma transfusion, the transition from closed to open conformation is irreversible (Walls et al., 2020).
Modern biochemistry and virology alone do not possess the tools to change the conformations of the glycoprotein in vivo or synthetically engineer antibodies that will fight Covid-19. There may be another way to change the conformation of the glycoprotein of SARS-CoV-2 and other viruses like it in order to produce vaccines faster and save millions of lives. Proteogenomics is a relatively new field of study, pioneered by Dr. Alexey I Nesvizhskii of the University of Michigan. In a paper detailing this field of study, Dr. Nesvizhskii details the use of proteomic databases, which possess both information about proteins and genes, and their potential application in alternative splicing. Alternative splicing refers to the study of specific portions of genes and identification of receptor sites using algorithmic modeling (Nesvizhskii, 2014). Rather than attack the virus directly, as has been done in the passed, genetic editing of the gene itself, which may be possible with new technologies like CRISPR and prime-base editing, could use binding sites identified using alternative splicing to stop the cleavage of the membrane fusion peptide thus keeping SARS-CoV-2 in the closed conformation and preventing Covid-19 from taking hold. Combating viruses like SARS-CoV-2 will be significantly easier in the future given the rapid development of more accurate gene editors and precise proteogenomic models. The key to combating future pandemics and viruses is understanding their pathological processes. With all of the current advances being made around the world, there is reason to hope that pandemics will be stopped much sooner in the future.
Nesvizhskii, A. I. (2014). Proteogenomics: concepts, applications and computational strategies. Nature Methods, 11(11), 1114–1125. https://doi.org/10.1038/nmeth.3144
Walls, A. C., Park, Y.-J., Tortorici, M. A., Wall, A., Mcguire, A. T., & Veesler, D. (2020). Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell, 281–292. https://doi.org/10.1101/2020.02.19.956581
World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it. World Health Organization. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it.
About the author:
Diego Suchenski Loustaunau is a sophomore at South High Community School in Worcester, Massachusetts in the United States. He is a member of his school’s Science Olympiad team, where he competes at the state level and in national invitationals. He is also on the math team where he competes regionally. His interests include protein biochemistry and computational modeling and he hopes to do research in those fields in the future.