Unveiling the antiviral capabilities of targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2

ABSTRACT The urgent need for effective treatments against emerging viral diseases, driven by drug-resistant strains and new viral variants, remains critical. We focus on inhibiting the human dihydroorotate dehydrogenase ( Hs DHODH), one of the enzymes in charge of pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance. We evaluated quinone-based compounds, discovering potent Hs DHODH inhibition (low nanomolar IC 50 ) and promising in vitro anti-SARS-CoV-2 activity (low micromolar EC 50 ). These compounds exhibited low toxicity, indicating potential for further development. Additionally, we employed computational tools like molecular docking and QSAR models to analyze protein-ligand interactions. These findings represent a significant step forward in the search for effective antiviral treatments and have great potential to impact the development of new broad-spectrum antiviral drugs.