Fragment linking yields orally active malaria N-myristoyltransferase inhibitors
- A hit's co-crystal structure with P. vivax NMT revealed a new binding mode, and cooperativity experiments flagged fragment pairs worth linking.
- Tuning the torsion of a phenolic ether linker balanced activity and selectivity, giving the early lead IMP-1002.
- IMP-1002 is orally active in a mouse malaria model against blood- and liver-stage parasites; an added fluorine also produced very potent human NMT inhibitors such as IMP-1088.
💡 Points Based on the abstract
Fragment linking opens a fresh binding mode in a crowded Plasmodium NMT chemotype space, which is welcome. The red flag is that the same fluorine also gives very potent human NMT inhibitors. Before advancing IMP-1002, I'd map the parasite-versus-host window carefully and test whether the linker torsion seen in the crystal persists in solution.