Beyond single-agent therapy: synergistic drug combinations and HSPG-Binding compounds as innovative strategies against SARS-CoV-2 variants

Since its emergence in 2020, COVID-19 has prompted extensive research and the development of multiple therapeutic options and vaccines. However, their efficacy has been challenged by ongoing viral evolution, leaving the optimal treatment and protection strategies for high-risk patients uncertain. Although the World Health Organization declared the end of the COVID-19 emergency in May 2023, SARS-CoV-2 continues to circulate endemically and remains a major cause of severe illness among high-risk groups. In this context, antiviral strategies remain a critical area of investigation. For these reasons, this doctoral thesis investigates alternative approaches against SARS-CoV-2 infection beyond using single-drug therapies, particularly focusing on synergistic drug combinations and host targeted antivirals. The study specifically explores the antiviral effectiveness of selected drug combinations with the aim to improve antivirals’ efficacy and reduce the emergence of viral resistance. In parallel, it also investigates a compound that binds heparan sulfate proteoglycans (HSPGs), which are important components of host cell surfaces involved in viral attachment and entry, as a strategy to inhibit the infection. Using in vitro cell-based models, the study assesses the antiviral activity, cytotoxicity, and synergistic effect of the chosen compounds against various SARS-CoV-2 variants. Overall, this work provides experimental evidence supporting the use of combination therapies and HSPG-binding compounds against viral entry as promising strategies to counteract viral evolution and enhance control over current and future SARS-CoV-2 variants.