Kinetic target-guided synthesis yields potent hydroxamate LasB inhibitors
- Guided by earlier crystal structures, kinetic target-guided synthesis was used to assemble inhibitors of the P. aeruginosa virulence factor elastase LasB.
- Extensive SAR gave hydroxamic acid inhibitors with very high potency and good selectivity over a panel of human off-targets.
- The compounds protected lung epithelial cells from LasB damage, showed in vivo efficacy, and reached lung exposure above their biochemical potency.
💡 Points
Using the enzyme itself to pick its best fragment pairs is a smart way into a metalloprotease pocket, and the lung PK above IC50 is exactly the data antivirulence programs usually lack. Hydroxamates still carry metabolic and zinc-binding baggage, so the off-target panel on other metalloenzymes is where I'd look first.