Epoxysuccinamide warheads hit SARS-CoV-2 PLpro hard, but a hydrazide linker undermines them
- Covalent PLpro inhibitors were designed by combining an epoxysuccinamide warhead for Cys-111 with groove-binding features borrowed from non-covalent inhibitors.
- The compounds showed very high enzymatic potency and strongly reduced viral titres in cell culture.
- The flexible hydrazide linker was cleaved by hepatic carboxylesterases, and alternative linkers did not work, so the series is metabolically limited.
💡 Points
A potent warhead that dies in the liver is a familiar story, and here the culprit is the very linker the chemistry needs for Cys-111 reach. I'd still keep the epoxysuccinamide in the toolbox for the next coronavirus, but the linker would be the first thing I'd redesign.
Discovery of Epoxysuccinates as Potent Covalent Inhibitors of SARS-CoV-2 Papain-like Protease ↗