Infectious diseases caused by viral pathogens remain a major global health threat. Undoubtedly, great progress has been achieved in this regard by the development of highly efficient direct acting antivirals (DAAs). However, there is no clinically approved antiviral treatment for the majority of viral infections. Additionally, the inhibition of viral replication is not always sufficient to prevent a progression of a disease caused by the infection. In the present work we addressed challenges in the development of antiviral therapies against two positive-sense single stranded RNA viruses ((+)ssRNA), hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While there are currently no antiviral regimens approved for clinical use against SARS-CoV-2, HCV infection can be nowadays efficiently cured by DAA treatment. However, several studies reported an acceleration of recurrent hepatocellular carcinoma in HCV-positive patients who underwent DAA therapy. On that account, we focused our first study on the identification of phenotypic changes driven by direct acting antivirals in hepatoma cells. We demonstrated that the treatment of liver-derived cells with sofosbuvir (SOF), a nucleoside analogue and a backbone of DAA therapy against HCV, activated the EGFR signalling pathway. The serine/threonine kinase profiling revealed several other kinases downstream of EGFR, also activated during SOF treatment. Our findings imply that SOF may have an impact on liver-related pathological processes via the promotion of EGFR signalling and its downstream pathways. Notably, the administration of EGFR inhibitor, erlotinib, during SOF treatment could prevent this effect. In our second study we established a human cell culture model for SARS-CoV-2 infection which allowed us to perform a comprehensive analysis of host translatome and proteome during the infection. We identified several components of translation, splicing and metabolism to be remarkably altered during the course of viral infection. By applying inhibitors we proved that these pathways represent druggable targets for antiviral therapy against SARS-CoV-2. Globally, our work can contribute to efforts to develop highly efficient therapies against two (+)ssRNA viruses which are currently affecting millions of people worldwide. Our findings provide a rationale for the development of a host-targeted therapy in combination with canonical pathogen-directed drugs as antiviral strategy able to clear viruses as well as resolve underlying diseases. Lastly, we rapidly identified novel host targets which may accelerate the drug discovery against the current pandemic.