DABPU-DE targeting host adipose triglyceride lipase provides broad-spectrum anti-coronavirus effects in vitro

This study aims to develop DABPU-DM derivatives that inhibit host adipose triglyceride lipase (ATGL) and identify the one with the highest broad-spectrum anti-coronaviral efficacy.

The antiviral effectiveness of DABPU-DM derivatives against representative viruses from all four genera within the subfamily Orthocoronavirinae was assessed using western blot, RT-qPCR, and immunofluorescence assay (IFA). The reduction in free fatty acid (FFA) and free glycerol (FG) levels following ATGL inhibition was measured with FFA and FG quantification assays. The antiviral effect of DABPU-DE with remdesivir against SARS-CoV-2, either alone or in combination, was evaluated by IFA, and their synergistic effect was analyzed using SynergyFinder 3.0.

Among six ATGL inhibitors, DABPU-DE exhibited the highest antiviral activity and safety, yielding a more favorable selectivity index than the other compounds. The enhanced antiviral effectiveness of DABPU-DE was linked to its diethylurea group, which increases ATGL binding affinity by enhancing hydrophobic and hydrogen-bonding interactions. In contrast, the weakest antiviral effect was observed with DABPU-DPh because its bulky diphenylurea group sterically hindered optimal binding and reduced interactions with ATGL. Additionally, combining DABPU-DE with remdesivir, which targets viral RNA-dependent RNA polymerase, produced strong, synergistic suppression of SARS-CoV-2 infection in Vero E6 cells.

Our findings indicate that the broad-spectrum anti-coronaviral activity of these compounds, particularly DABPU-DE, provides a promising preclinical foundation. This study underscores the potential of ATGL-targeted interventions as a viable strategy for managing current SARS-CoV-2 variants and preparing for future coronavirus outbreaks.