Viruses pose a significant threat to global public health, leading to millions of infections and substantial societal and economic burdens. The urgent need for effective antiviral therapies is underscored by the limitations of current treatments, which often target a narrow range of viral pathogens. This thesis explores two innovative strategies for antiviral discovery, with a primary focus on targeting viral RNA and inhibiting viral attachment receptors.
The first approach explores the targeting of viral RNA, an underutilized area in antiviral development. Our findings demonstrate that geneticin, an aminoglycoside antibiotic, effectively inhibits the -1 programmed ribosomal frameshifting mechanism of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Remarkably, we observed sustained antiviral activity ex vivo, coupled with a high resistance barrier. Building on these findings, and especially on the identification of the binding pocket, we uncovered additional small molecules that act similarly with an in silico approach. Notably, one of these compounds now stands as the most potent inhibitor known to target the -1 PRF mechanism of SARS-CoV-2, highlighting a novel class of potent inhibitors.
The second strategy involves investigating viral attachment receptors used by respiratory viruses to design a pan-respiratory antiviral strategy. As these viruses used sialic acid or heparan sulfate to initiate viral entry, the combination of modified β-cyclodextrins mimicking these receptors was performed. Clinical isolates of Human Parainfluenza 3 viruses were used initially as they used both attachment receptors. To overcome an antagonistic effect observed in vitro explained by an in silico approach, we synthesized a novel dual-active macromolecule that mimics both receptors in a single molecule, resulting in enhanced potency. This innovative compound exhibited broad-spectrum antiviral activity ex vivo against major respiratory viruses, including SARS-CoV-2, Influenza A H1N1, and respiratory syncytial virus with promising in vivo efficacy.
In summary, this thesis integrates multidisciplinary approaches, including chemical synthesis, biological assays, and in silico modeling, to advance the field of antiviral research. By exploring novel mechanisms, we contribute valuable insights and potential solutions to combat viral infections effectively.