PDIA3 inhibitors from an N-hydroxyindole series act as host-targeted antivirals against respiratory viruses
- PDIA3, an ER oxidoreductase involved in folding glycosylated viral envelope proteins, is an underexplored host target for antivirals.
- A new N-hydroxyindole-2-carboxamide class, exemplified by AV22, inhibits PDIA3 and shows broad activity against major human respiratory viruses.
- In coronavirus-infected cells AV22 raised release of non-infectious particles and reduced disulfide bond formation in spike.
💡 Points
Host-directed antivirals dodge resistance but live or die on the therapeutic window, because PDIA3 does real work in uninfected cells. An N-hydroxy group is also a flag for me: metal binding and metabolic liability can both bite. I'd look first at cytotoxicity margins and microsomal stability.