Double-edged swords: Anthracyclines inhibit -1 programmed ribosomal frameshifting and restrict HCoV-OC43 infection but show cytotoxicity

Abstract

Human coronavirus OC43 (HCoV-OC43) constitutes one of the most common causes of the seasonal cold but can also cause severe disease among elderly and immuno-compromised. Currently, there are no approved antiviral drugs to combat HCoV-OC43 infection. Coronaviruses are positive-sense single-stranded RNA (+ssRNA) viruses and utilize -1 programmed ribosomal frameshifting (-1 PRF) to produce the correct stoichiometry of viral protein components. Due to its high conservation, the ribosomal frameshifting stimulation element (FSE) is a promising target for antiviral drug discovery. Aminoglycosides and anthracyclines interact with structured nucleic acids and some of these compounds affect -1 PRF in SARS-CoV-2. To get a comprehensive view of their putative efficacy, we examined all commercially available aminoglycosides and anthracyclines for their ability to affect -1 PRF in HCoV-OC43 and their potential to reduce HCoV-OC43 infection. Of 25 candidates tested, we identified 3 anthracyclines (Idarubicin, Nogalamycin and Daunorubicin) to reduce HCoV-OC43 -1 PRF using in vitro assays. We further demonstrate that the active anthracyclines, but not the inactive anthracycline, bind to the HCoV-OC43 FSE. The active anthracyclines did not significantly affect -1 PRF in SARS-CoV-2, suggesting differences in the interactions of the anthracyclines and FSEs, despite being relatively conserved in HCoV-OC43 and SARS-CoV-2 RNAs. Interestingly, these potent anthracyclines also significantly reduced HCoV-OC43 infection in human host cells. Although, the anthracyclines show some toxicity and introduce lesions in cellular DNA they could constitute an important scaffold for further antiviral development, with the aim to increase efficacy and reduce toxicity. Author summaryThe recent Covid-19 pandemic caused by SARS-CoV-2 showed the need for functional antivirals to immediately combat infections at the onset of future pandemics. In addition to SARS-CoV-2, four other human coronaviruses can cause mild to severe infection. Among those is HCoV-OC43, a coronavirus particularly troublesome for immunocompromised patients. Despite this clinical relevance, no approved antiviral therapies are currently available for the prevention or treatment of HCoV-OC43 infections. In this work, we have identified a subset of anthracyclines (Idarubicin, Nogalamycin and Daunorubicin) that selectively and significantly reduce HCoV-OC43 infection. In contrast to a non-active anthracycline, the same anthracyclines that reduce infection also reduce ribosomal frameshifting and interact with a structured RNA in the viral RNA-genome. Interestingly, Idarubicin, a clinically used anticancer drug, shows selectivity for HCoV-OC43, but not for SARS-CoV-2 RNA. Our work demonstrates that anthracyclines could be important for pandemic preparedness and serve as attractive scaffolds when developing new antivirals targeting coronaviruses.