Ribosomal Frameshifting

Overview of Ribosomal Frameshifting

Ribosomal frameshifting, also known as translational frameshifting, refers to the phenomenon where the amino acid sequence translated during protein synthesis is different from the original codon sequence due to the misalignment and sliding of ribosomes. In normal cells, ribosomes read the genetic information in mRNA, which is organized in three nucleotide units (codons) and synthesized proteins in a continuous, one-directional manner from the 5' to 3' end. However, when ribosomal frameshifting occurs, the translated protein contains different amino acids, resulting in changes in protein structure and function. This phenomenon is crucial in many biological processes. Some viruses use ribosomal frameshifting to generate two or more overlapping open reading frames and encode additional proteins. This process, called programmed ribosomal frameshifting (PRF), can cause viral death or a decrease in the number of viruses if their shifting efficiency is altered.

Fig. 1 Schematic diagram of Ribosomal frameshifting.¹

Developing Antiviral Drugs Using Ribosomal Frameshifting

The frequency of ribosomal frameshifting varies across different organisms. Ribosomal frameshifting is not only a cellular process, but also plays an important role in the replication of many viruses. Viral genomes are typically small and require ribosomal frameshifting to translate their own genomes and produce the necessary proteins. In addition, some viruses use ribosomal frameshifting to encode multifunctional proteins, which control various biological processes in cells. Therefore, any compound that can inhibit this frameshifting mechanism may be developed as an antiviral drug. For example, researchers have identified a small molecule compound, merafloxacin, which efficiently inhibits frameshifting using a fluorescent protein reporting system combined with high-throughput screening technology. Bhatt et al. demonstrated that merafloxacin significantly inhibits SARS-CoV-2 replication at the cellular level (Vero E6 cells). The mechanism by which merafloxacin inhibits frameshifting is not clear, but it may directly affect the binding of ribosomes and viral RNA or inhibit endogenous regulatory proteins. In addition, Ahn et al. identified a novel compound, 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline (KCB261770), from 9689 small molecules, which can inhibit MERS-CoV frameshifting and cell-level replication. This compound also inhibits frameshifting of SARS-CoV and SARS-CoV-2, and has broad-spectrum anti-coronavirus activity.

Fig. 2 Inhibitory effects of furo[2,3-b]quinoline derivatives on MERS-CoV frameshifting.²

Overall, ribosomal frameshifting is a highly important phenomenon in gene translation, with broad influence and application in regulating and controlling life processes. Through in-depth study and exploration of ribosomal frameshifting, we can better understand biological translation processes, various cellular behaviors, and virus growth mechanisms, laying a solid foundation for the future development of human health and medical treatment. Creative Biolabs specializes in ribosome research, providing a wide range of services to global customers, including but not limited to Ribosomal Transcriptome services and Ribosomal Proteomics services. If you are interested in our ribosome services, do not hesitate to contact us for more information.

References

1. Rampersad, Sephra, and Paula Tennant. "Replication and expression strategies of viruses." Viruses (2018): 55.
2. Ahn, Dae-Gyun, et al. "A novel frameshifting inhibitor having antiviral activity against zoonotic coronaviruses." Viruses 13.8 (2021): 1639.