Nortropinone-based inhibitors hit both host cathepsin L and coronavirus 3CL proteases
- Structure-guided inhibitors built on a nortropinone scaffold target human cathepsin L, needed for viral entry, and the 3C-like proteases of SARS-CoV-2 and MERS-CoV.
- The compounds were non-cytotoxic and potent against all three enzymes, with the lead compound strongest against cathepsin L.
- The lead suppressed SARS-CoV-2 infection in cell culture with a wide safety margin.
- Co-crystal structures with both viral proteases confirmed the binding mode and guided optimization.
💡 Points Based on the abstract
Dual targeting is attractive, but I'd want to know which enzyme actually drives the antiviral effect in cells. Without a cathepsin L knockout or a 3CLpro-resistant virus, it's unresolved. Host cathepsin L inhibition also raises off-target and tolerability questions that a cell-culture margin can't answer. Next step: in vivo PK and a comparison against established 3CLpro inhibitors.