Development of N-Hydroxyindole-2-Carboxamides as New Host-Targeted Broad-Spectrum Antiviral Agents Against Human Respiratory Viruses.

Endoplasmic reticulum (ER) oxidoreductases are promising targets for host-targeted antiviral agents (HTAs) because of their essential role in protein folding, including the maturation of viral proteins. Human protein disulfide isomerase family member A3 (PDIA3) is involved in the folding of N-glycosylated client proteins, including viral envelope proteins, making it an attractive but underexplored antiviral target. Here, we describe the discovery of a novel N-hydroxyindole-2-carboxamide class of PDIA3 inhibitors, exemplified by compound AV22 (1o), which effectively inhibits PDIA3 activity and exerts broad-spectrum antiviral activity against major human respiratory viruses. Mechanistic studies indicated that AV22 (1o) increased the release of non-infectious coronavirus particles and reduced disulfide bond formation in the coronavirus spike protein, indicating that its antiviral effect stems from interference with PDIA3 activity. This new class of HTAs provides promising leads for drug discovery targeting viral envelope protein maturation vulnerabilities and is suitable for developing new BSAs.