MicroRNA Mimics or Inhibitors as Antiviral Therapeutic Approaches Against COVID-19

Abstract

Coronaviruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the coronavirus disease 2019 (COVID-19) pandemic, present a significant threat to human health by inflicting a wide variety of health complications and even death. While conventional therapeutics often involve administering small molecules to fight viral infections, small non-coding RNA sequences, known as microRNAs (miRNAs/miR-), may present a novel antiviral strategy. We can take advantage of their ability to modulate host-virus interactions through mediating RNA degradation or translational inhibition. Investigations into miRNA and SARS-CoV-2 interactions can reveal novel therapeutic approaches against this virus. The viral genomes of SARS-CoV-2, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) were searched using the Nucleotide Basic Local Alignment Search Tool (BLASTn) for highly similar sequences, to identify potential binding sites for miRNAs hypothesized to play a role in SARS-CoV-2 infection. miRNAs that target angiotensin-converting enzyme 2 (ACE2), the receptor used by SARS-CoV-2 and SARS-CoV for host cell entry, were also predicted. Several relevant miRNAs were identified, and their potential roles in regulating SARS-CoV-2 infections were further assessed. Current treatment options for SARS-CoV-2 are limited and have not generated sufficient evidence on safety and efficacy for treating COVID-19. Therefore, by investigating the interactions between miRNAs and SARS-CoV-2, miRNA-based antiviral therapies, including miRNA mimics and inhibitors, may be developed as an alternative strategy to fight COVID-19.

Figure 1

Potential therapeutic applications of miRNAs. Through miRNA enhancement, mRNA expression and translation that is upregulated during viral infection can be repressed. In contrast, through miRNA suppression, mRNA expression and translation that is downregulated during viral infection can be restored. miRNA microRNA, RISC RNA-induced silencing complex, AGO argonaute, TRBP trans-activation response RNA-binding protein, PACT protein kinase RNA activator

Figure 2

Potential interactions between miRNAs and viral infection. Host-derived miRNA transcripts can serve as substrates for the endonuclease Dicer to produce mature miRNA, which can complex with the RISC. The miRNAs can be sequestered by the viral genome to derepress cellular targets or stabilize the genome for replication (a), induce degradation or translational inhibition of viral RNA (b), or host mRNA to modulate cellular pathways relevant for the viral infection (c). The virus can also interact directly with the host genome to alter the transcriptome and modulate miRNA expression to induce pro- or antiviral cellular effects (d). Some viruses can also encode viral miRNAs that can target both host and viral RNA (e). miRNA microRNA, RISC RNA-induced silencing complex

Figure 3

Overview of the proposed miRNA-based antiviral therapeutic approach against SARS-CoV-2 infection. Flowcharts outlining the strategies used to identify miRNAs that bind to the SARS-CoV-2 viral genome (a) or the ACE2 receptor (b) for the development of miRNA-based therapeutics are presented. ACE angiotensin-converting enzyme, BLASTn Nucleotide Basic Local Alignment Search Tool, MERS-CoV Middle East respiratory syndrome coronavirus, miRNA/miR- microRNA, SARS-CoV severe acute respiratory syndrome coronavirus, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, UTR untranslated region

Figure 4

Number of predicted miRNA binding sites in the SARS-CoV-2, SARS-CoV, and MERS-CoV genomes. A heat map indicating the number of binding sites predicted in each viral genome is presented (values ranging from 0 to 21). Binding sites were predicted at locations with 100% complementarity to the hsa-miRNA seed site sequence using BLASTn. miRNAs are listed in decreasing order of the total number of binding sites predicted in the SARS-CoV-2 genome. BLASTn Nucleotide Basic Local Alignment Search Tool, MERS-CoV Middle East respiratory syndrome coronavirus, miRNA/miR- microRNA, SARS-CoV severe acute respiratory syndrome coronavirus, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

Figure 5

Schematic representation of predicted miRNA binding sites in the SARS-CoV-2 genome. The location of potential binding sites in the SARS-CoV-2 genome for select miRNA of interest, including the top three most abundant miRNAs in lung epithelial A549 cells (miR-16, miR-29, and miR-30), miR-24, and miR-200 are presented. miRNA/miR- microRNA, ORF open reading frame, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, UTR untranslated region

Figure 6

miRNAs predicted to bind to the 3′-UTR of ACE2. The miRDB, DIANA microT-CDS, and TargetScan databases were used to predict miRNAs that bind to the 3′-UTR of ACE2. Searches included both highly and poorly conserved sites, as well as 6mer, 7mer, 8mer, and 9mer binding sites. miRNAs in bold were predicted to have more than one miRNA binding site. Numbers in red indicate the total number of miRNAs predicted in each group. ACE2 angiotensin-converting enzyme 2, miRNA/miR- microRNA, UTR untranslated region