In silico analysis suggests the RNAi-enhancing antibiotic enoxacin as a potential inhibitor of SARS-CoV-2 infection

Amirhossein Ahmadi,Sharif Moradi

doi:10.1038/s41598-021-89605-6

Abstract

COVID-19 has currently become the biggest challenge in the world. There is still no specific medicine for COVID-19, which leaves a critical gap for the identification of new drug candidates for the disease. Recent studies have reported that the small-molecule enoxacin exerts an antiviral activity by enhancing the RNAi pathway. The aim of this study is to analyze if enoxacin can exert anti-SARS-CoV-2 effects. We exploit multiple computational tools and databases to examine (i) whether the RNAi mechanism, as the target pathway of enoxacin, could act on the SARS-CoV-2 genome, and (ii) microRNAs induced by enoxacin might directly silence viral components as well as the host cell proteins mediating the viral entry and replication. We find that the RNA genome of SARS-CoV-2 might be a suitable substrate for DICER activity. We also highlight several enoxacin-enhanced microRNAs which could target SARS-CoV-2 components, pro-inflammatory cytokines, host cell components facilitating viral replication, and transcription factors enriched in lung stem cells, thereby promoting their differentiation and lung regeneration. Finally, our analyses identify several enoxacin-targeted regulatory modules that were critically associated with exacerbation of the SARS-CoV-2 infection. Overall, our analysis suggests that enoxacin could be a promising candidate for COVID-19 treatment through enhancing the RNAi pathway.

Highlights

COVID-19 has currently become the biggest challenge in the world
Since enoxacin has been reported to exert its anti-viral activity by means of enhancing the RNA interference (RNAi) pathway through binding and stimulating the activity of TAR RNA binding protein (TRBP), the physical partner of DICER23,33, we first investigated if the singlestranded RNA genome of SARS-CoV-2 might be processed by the RNAi machinery
These results strongly suggest that the SARS-CoV-2 genome intrinsically harbors multiple hairpin structures which could be processed by DICER/TRBP complex, allowing for the efficient degradation of the coronavirus RNA genome through the RNAi pathway

Summary

Introduction

COVID-19 has currently become the biggest challenge in the world. There is still no specific medicine for COVID-19, which leaves a critical gap for the identification of new drug candidates for the disease. It can lead to a potentially lifethreatening immune reaction called the cytokine release syndrome or cytokine storm which is resulted from an exaggerated immune response (i.e. a hyperactive IFN-mediated response) to the viral infection[16] This immune overreaction is injurious to the host cells and might be induced by the SARS-CoV-2 infection[17]. Is typically more active in embryonic and non-mature (e.g. stem and progenitor) cells[18] It involves the efficient degradation of the large viral RNAs which form secondary double-stranded structures thereby serving as substrates of the RNAi p athway[18]. Quinolones are known to typically inhibit DNA replication by targeting bacterial DNA g yrases[21], a growing body of evidence has revealed that some members of this family of antibiotics could inhibit viral helicases, attenuate cytokine production and pro-inflammatory reactions[22], and more importantly enhance the RNAi process as an inflammation-free innate immune defense against viral infections[23]

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