Stripping the Peptide Backbone From Boronic Acid Malaria Protease Inhibitors Keeps Enzyme Potency
- PfSUB1 is a parasite protease needed for merozoites to exit infected red blood cells, making it an attractive antimalarial target.
- Docking guided replacement of the P1-P2 dipeptide in peptidic boronic acids with a 3-aminomethylphenylboronic acid core, reducing peptide character.
- Adding a meta-carboxylate to engage Lys138 sharply boosted enzyme inhibition, and an N-acylsulfonamide swap kept comparable potency.
- Whole-parasite activity stayed modest, pointing to membrane permeability as the next hurdle.
💡 Points Based on the abstract
Boronic acids on a benzylamine core trade peptide-like recognition for a covalent warhead plus one salt bridge, so I'd want to know how much of the potency is just boron reactivity. Check selectivity against human serine proteases and run a non-boron control. The permeability problem is predictable: a carboxylate or acylsulfonamide next to a boronic acid is very polar, so test prodrug or ester masking early.
📄 Paper · bioRxiv ↗ Discovery of P1-P2 depeptidized boronic acid based Plasmodium falciparum SUB1 inhibitor