Synergistic antiviral effect of host Adipose Triglyceride Lipase-directed DABPU-DE with coronavirus RNA-dependent RNA polymerase-targeting remdesivir on feline infectious peritonitis virus

Feline infectious peritonitis virus (FIPV) poses a significant threat to cats worldwide. Besides the limited development of antiviral drugs that mainly target virus proteins, concerns about resistance to mutant strains - similar to those seen in human and other mammalian viruses - remain high. Therefore, addressing these challenges involves developing innovative antiviral therapies, such as host-directed treatments that target host cell processes essential for viral replication. FIPV infection induced distinctive dynamics of lipid droplet (LD) remodelling, characterized by an increase in LD abundance from early to mid-infection, followed by a subsequent decline. Phosphorylated hormone-sensitive lipase, a key mediator of LD hydrolysis and fatty-acid release, became activated after the mid-infection phase, potentially contributing to elevated intracellular fatty-acid availability during late infection. Notably, atglistatin (DABPU-DM) and its derivatives robustly suppressed FIPV replication in Crandell-Rees feline kidney (CRFK) and feline macrophage Fcwf-4 cells, coincident with preservation of LD integrity and inhibition of LD breakdown. Among these compounds, DABPU-DE had the best selectivity index (686.0±35.2) against FIPV, with a higher half-maximal cytotoxic concentration (274.4±3.6 µM) and a lower half-maximal inhibitory concentration (0.4±0.02 µM). Moreover, combining DABPU-DE (0.18 µM) with remdesivir (1.35 µM), a viral RNA-dependent RNA polymerase inhibitor, showed a very strong synergistic effect (CI=0.09 and Bliss synergy score=14.46±1.80) in inhibiting FIPV replication in CRFK cells, even at lower doses than either drug alone. In conclusion, DABPU-DE is a promising antiviral candidate for FIPV, and its synergistic effect with remdesivir warrants further research in cats infected with FIPV.