Ribavirin is a guanosine analog with broad-spectrum antiviral activity against RNA viruses. Based on this, we aimed to show the anti-SARS-CoV-2 activity of this drug molecule via in vitro, in silico, and molecular techniques. Ribavirin showed antiviral activity in Vero E6 cells following SARS-CoV-2 infection, whereas the drug itself did not show any toxic effect over the concentration range tested. In silico analysis suggested that ribavirin has a broad-spectrum impact on SARS-CoV-2, acting at different viral proteins. According to the detailed molecular techniques, ribavirin was shown to decrease the expression of TMPRSS2 at both mRNA and protein levels 48 h after treatment. The suppressive effect of ribavirin in ACE2 protein expression was shown to be dependent on cell types. Finally, proteolytic activity assays showed that ribavirin also showed an inhibitory effect on the TMPRSS2 enzyme. Based on these results, we hypothesized that ribavirin may inhibit the expression of TMPRSS2 by modulating the formation of inhibitory G-quadruplex structures at the TMPRSS2 promoter. As a conclusion, ribavirin is a potential antiviral drug for the treatment against SARS-CoV-2, and it interferes with the effects of TMPRSS2 and ACE2 expression.

Thanks to its intrinsic properties, two-dimensional (2D) bismuth (bismuthene) can serve as a multimodal nanotherapeutic agent for lung cancer acting through multiple mechanisms, including photothermal therapy (PTT), magnetic field-induced hyperthermia (MH), immunogenic cell death (ICD), and ferroptosis. To investigate this possibility, we synthesized bismuthene from the exfoliation of 3D layered bismuth, prepared through a facile method that we developed involving surfactant-assisted chemical reduction, with a specific focus on improving its magnetic properties. The bismuthene nanosheets showed high in vitro and in vivo anti-cancer activity after simultaneous light and magnetic field exposure in lung adenocarcinoma cells. Only when light and magnetic field are applied together, we can achieve the highest anti-cancer activity compared to the single treatment groups. We have further shown that ICD-dependent mechanisms were involved during this combinatorial treatment strategy. Beyond ICD, bismuthene-based PTT and MH also resulted in an increase in ferroptosis mechanisms both in vitro and in vivo, in addition to apoptotic pathways. Finally, hemolysis in human whole blood and a wide variety of assays in human peripheral blood mononuclear cells indicated that the bismuthene nanosheets were biocompatible and did not alter immune function. These results showed that bismuthene has the potential to serve as a biocompatible platform that can arm multiple therapeutic approaches against lung cancer.