Ever since the beginning of the current COVID-19 pandemic, clinicians have worked tirelessly to better understand the new SARS-CoV-2 virus and its pathobiology. Their overall goal is the discovery of safe, effective therapeutic interventions. One central tactic being employed by scientists is the targeting of enzymes that are key to virus-host interaction and replication, by using biologics and small molecules.
A significant family of enzymes - N6-methyladenosine methyltransferases – is currently under investigation for its role in the SARS-CoV-2 life cycle. RNA methylation forming N6-methyladenosine (m6A) in mRNA accounts for most of the mRNA internal modification in eukaryotes. This has been discovered in the viral RNA replicating inside host nuclei.
Modifications in viral RNA stability control have been found to be a mechanism for evading host immune response. Depending on the specific viral species and lifestyles, m6A modiﬁcations have the potential to positively affect RNA replication, or alternatively, negatively affect RNA assembly.
Because of these pro- or antiviral functions, m6A modifications offer new potential targets for antiviral intervention.
There are two recombinant versions of essential SARS-CoV-2 active protein targets with potential for use in COVID-19 therapeutics:
- METTL3/METTL14, Active (M323-380G) - full-length recombinant human METTL3/METTL14 complex was found to be expressed by baculovirus in Sf9 insect cells using an N-terminal GST tag.
- METTL16, Active (M336-380G) - recombinant full-length human METTL16 was found to be expressed by baculovirus in Sf9 insect cells using an N-terminal GST tag.
m6A in mRNAs and other RNA polymerase II-derived transcripts are mainly installed via the METTL3-METTL14 methyltransferase (MTase) complex. Here, METTL3 acts as the catalytic core and METTL14 forms an allosteric activator while also binding to the target RNA.
The enzyme occurs as a stable complex within cells, and it is linked with WTAP, another non-catalytic component which seems to considerably increase the binding affinity of METTL3 for RNA. WTAP is not required for MTase activity of the heterodimer in vitro, however.
SARS-CoV-2’s RNA genome contains over 50 potential m6A sites, based on the existence of particular sequence motifs for m6A modification by METTL3-METTL14, including GGACA, GGACU and GGACC. As a result, ≥0.64% of adenosines, or 0.18% of bases, in SARS-CoV-2 RNA could potentially be m6A.
Adjusting the level of m6A through modulation of the MTase activity of a METTL3-METTL14 complex may lead to major functional changes in the virus, including deficient replication or enhanced susceptibility to host defense.
As well as the already well-characterized METTL3-METTL14 complex, a further mammalian methyltransferase - METTL16 - is also recognized for its role in m6A deposition. The single m6A in the U6 small nuclear RNA (snRNA) (an snRNA used in splicing) is introduced by METTL16. Additionally, METTL16 catalyzes m6A formation in U6-like sequences in the MAT2A mRNA, encoding the enzyme necessary for S-adenosylmethionine biosynthesis.
METTL16 also catalyzes m6A formation in a handful of other mRNAs and non-coding RNAs. It is believed that comparable modifications on viral RNAs may influence the viral gene expression, virus replication and progeny virion generation.
Figure 4. Activity of m6A methyltransferases METTL3-METTL14 (SignalChem Catalog No. M323-380G, A), and METTL16 (SignalChem Catalog No. M336-380G, B), as detected in Methyltransferase-GloTM assays. Image Credit: SignalChem Biotech Inc.
As a global leader in both cell signaling and protein engineering, SignalChem has been undertaking research on the new coronavirus since the initial outbreak of the virus. Its scientists have invested considerable resources in an investigation of SARS-CoV-2’s protein interaction map to engineer active recombinant human proteins and SARS-CoV-2.
SignalChem is working to provide other researchers with these essential pieces of the puzzle, which are key to the development of drug discovery research projects worldwide.
New developments in engineering technology and AI drug development software have aided SignalChem in initiating projects and developing expression systems of key COVID-19 related proteins. These include hot drug targets such as proteases and non-structural proteins (NSPs).
Catalytically active proteins such as these are considered to be fully functional and ready to be employed in research projects, and the development of drugs directed against SARS-CoV-2, and future coronavirus infections.
About SignalChem Biotech Inc.
SignalChem is a biotech company focused on the research, development, and production of innovative and high-quality human recombinant cell signaling products.
Throughout the years, Signalchem has capitalized on its core expertise in cellular signaling, molecular biology, and protein biochemistry to generate more than 2,000 functional protein products and has established itself as the leader in the industry to produce highly active human recombinant signaling enzymes, especially protein kinases, disease-related mutant kinases, lipid kinases, epigenetic enzymes, ubiquitination-related enzymes, and neurodegenerative disease-related enzymes and proteins.
SignalChem strives to support scientists in academia, pharma and biotech companies around the world by creating effective research tools to advance the basic research in life sciences and to facilitate the efforts in drug discovery and development.
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