miR-24-3p Is Antiviral Against SARS-CoV-2 by Downregulating Critical Host Entry Factors

Viruses. 2024 Nov 28;16(12):1844. doi: 10.3390/v16121844.

Abstract

Despite all the progress in treating SARS-CoV-2, escape mutants to current therapies remain a constant concern. Promising alternative treatments for current and future coronaviruses are those that limit escape mutants by inhibiting multiple pathogenic targets, analogous to the current strategies for treating HCV and HIV. With increasing popularity and ease of manufacturing of RNA technologies for vaccines and drugs, therapeutic microRNAs represent a promising option. In the present work, miR-24-3p was identified to inhibit SARS-CoV-2 entry, replication, and production; furthermore, this inhibition was retained against common mutations improving SARS-CoV-2 fitness. To determine the mechanism of action, bioinformatic tools were employed, identifying numerous potential effectors promoting infection targeted by miR-24-3p. Of these targets, several key host proteins for priming and facilitating SARS-CoV-2 entry were identified: furin, NRP1, NRP2, and SREBP2. With further experimental analysis, we show that miR-24-3p directly downregulates these viral entry factors to impede infection when producing virions and when infecting the target cell. Furthermore, we compare the findings with coronavirus, HCoV-229E, which relies on different factors strengthening the miR-24-3p mechanism. Taken together, the following work suggests that miR-24-3p could be an avenue to treat current coronaviruses and those likely to emerge.

Keywords: COVID-19; HCoV-229E; NRP1; NRP2; SARS-CoV-2; SREBP2; furin; miR-24; miR-24-3p; microRNA.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • COVID-19* / virology
  • Chlorocebus aethiops
  • Down-Regulation
  • Furin / genetics
  • Furin / metabolism
  • HEK293 Cells
  • Host-Pathogen Interactions / genetics
  • Humans
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • SARS-CoV-2* / drug effects
  • SARS-CoV-2* / genetics
  • SARS-CoV-2* / physiology
  • Vero Cells
  • Virus Internalization* / drug effects
  • Virus Replication* / drug effects

Substances

  • MicroRNAs
  • MIRN24 microRNA, human
  • Furin
  • Antiviral Agents
  • FURIN protein, human

Grants and funding

This research was funded by the Canadian Institutes for Health Research (CIHR), grant number 221125 and the Natural Sciences and Engineering Council of Canada (NSERC), 210719.