SARS-CoV-2 RNA Structures Reveal Potential Drug Targets

SARS-CoV-2 RNA Structures Reveal Potential Drug Targets

Throughout human history, infectious diseases caused by bacteria and viruses have always existed. In the past 18 years, severe acute respiratory syndromes caused by coronaviruses (including MERS and SARS) have caused many deaths worldwide. The recent persistence of the COVID-19 pandemic, which has killed more than one million people, indicates the urgent need for new methods to combat coronavirus infection.

Recently, researchers from the University of Groningen, the International Institute of Molecular and Cell Biology in Warsaw, and Leiden University studied the RNA genome structure of SARS-CoV-2 coronavirus in detail. The RNA structure is a potential target for the development of antiviral drugs. The results were published in the journal Nucleic Acid Research.

3D modeling of SARS-CoV-2 RNA structured segments and identification of druggable pockets. Figure 1. 3D modeling of SARS-CoV-2 RNA structured segments and identification of druggable pockets. (Ilaria Manfredonia et al., 2020)

COVID-19 is caused by SARS-CoV-2, a β-coronavirus with a linear single strand positive RNA genome. Similar to other RNA viruses, the SARS-CoV-2 RNA structure is expected to play a key role in the replication of coronavirus in human cells. RNA viruses, responsible for numerous deadly diseases (such as Hepatitis C, SARS, AIDS, Dengue and Ebola), are characterized by higher mutation rates compared to DNA viruses, allowing them to rapidly evolve and adapt. Due to their high mutation rates, RNA viruses can rapidly develop resistance to vaccines and drugs by slightly changing their core proteins. By comparison, certain RNA structures formed in the context of viral RNA genomes are well preserved, despite changes in the underlying encoded amino acid sequence, making them valuable therapeutic targets.

In fact, inhibition of viral replication by RNA-targeting small molecule drugs has been shown to be feasible for other RNA viruses, such as the hepatitis C virus (HCV), SARS-CoV, human immunodeficiency virus (HIV), and influenza A virus (IAV). In addition, the identification of highly-conserved weakly structured regions within viral RNA genomes may be helpful for the design of oligonucleotide-bases antiviral therapeutics. Despite this importance, only a few functional coronavirus RNA elements have been studied so far. Therefore, researchers from IIMCB, together with scientists from Groningen University and Leiden University, have used various advanced technologies to extensively characterize the structure of the SARS-CoV-2 RNA genome.

In this work, researchers provide the first experimental characterization of the full-length genome of a coronavirus through SHAPE and DMS mutational profiling (SHAPE-MaP and DMS-MaPseq) analyses, using the novel SARS-CoV-2 virus as a model. They obtained a single-base resolution map of base reactivities that enabled them to model the secondary structure of 87 well-defined structure elements throughout the entire SARS-CoV-2 genome. Among them, at least 10.2% are under strong evolutionary selection pressure among coronaviruses, indicating functional relevance.

Pocket like epitopes have been found in some RNA structures, so small molecules can be designed to target these pockets, thus blocking the function of viral RNA. In addition, because many of the structures are conserved among different coronaviruses, it means that drugs targeting SARS-CoV-2 may also be effective against future new strains of viruses. Their analysis also identified conserved sites of persistent single-strandedness in the SARS-CoV-2 genome in vivo. These regions might be ideal targets for the design of antisense oligonucleotide therapeutics (ASO), already proven to represent a promising method for the treatment of infections by other RNA viruses.

Overall, this collaborative study lays a solid foundation for future work aimed at developing potential small molecule drugs to treat SARS-CoV-2 infection and other coronavirus infections.

Reference

  1. Ilaria Manfredonia et al., Genome-wide mapping of SARS-CoV-2 RNA structures identifies therapeutically-relevant elements, Nucleic Acids Research (2020).

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