Discovery of P1-P2 depeptidized boronic acid based Plasmodium falciparum SUB1 inhibitor

A meta-carboxylate–bearing depeptidized boronic acid (compound 3a) inhibits Plasmodium falciparum PfSUB1 with an IC50 of 10.2 nM, linked to interactions with Lys138.

• Why it matters: PfSUB1 is essential for parasite egress, and peptidic boronic acids face drug-likeness limits, creating a need for less peptidic, more developable inhibitors.
• What they did: Using docking with peptidic boronic acids, the team replaced the P1–P2 dipeptide with a 3-aminomethylphenylboronic acid core and ran SAR focused on Lys138, including carboxylate and N-acylsulfonamide variants.
• The result: In blood-stage assays against the 3D7 strain, leading depeptidized boronic acids showed low-micromolar growth inhibition, and the SAR supports rational non-peptidic PfSUB1 inhibitor design.

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