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 (HsDHODH), one of the main enzymes responsible for pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance. We evaluated naphthoquinone fragments, discovering potent HsDHODH inhibition with IC 50 ranging from 48 to 684 nM, and promising in vitro anti-SARS-CoV-2 activity with EC 50 ranging from 1.2 to 2.3 μM. These compounds exhibited low toxicity, indicating potential for further development. Additionally, we employed computational tools such as molecular docking and quantitative structure−activity relationship (QSAR) models to analyze protein−ligand interactions, revealing that these naphthoquinones exhibit a protein binding pattern similar to brequinar, a potent HsDHODH inhibitor. 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.

Introducing CRAFT: The Center for Research and Advancement in Fragments and molecular Targets

“…The journey toward CRAFT began in 2013, when the teams led by Professors Nonato and Emery at USP embarked on a fruitful collaboration aimed at comprehending the structural and functional characteristics of the enzyme dihydroorotate dehydrogenase (DHODH) across various species. This effort utilized diverse biophysical chemical tools, leading to the discovery of nanomolar inhibitors for DHODH in different species. − …”