Thiophene-linked nucleotide analogues selectively block malaria purine salvage enzymes
- Parasite HG(X)PRT enzymes resemble the human enzyme at the active site, so modeling and conformational analysis guided a rigid thiophene core that orients the phosphate-mimicking groups.
- A C5 sulfonyl group greatly raised potency against the P. falciparum enzyme, and lead compound 66 was strongly selective over the human enzyme.
- Linker length shifted species preference, with compound 63 best against P. vivax; cell activity stayed weak, making intracellular delivery or prodrugs the main hurdle.
💡 Points Based on the abstract
Nanomolar enzyme potency with weak cell activity is the classic phosphate-mimic trap: the charged groups that buy affinity cost permeability. Before investing in prodrugs, it is worth working out whether the cell gap reflects uptake or competition with high salvage flux, and benchmarking against earlier acyclic nucleoside phosphonate inhibitors of the same enzymes.