Peptidic Phosphonates as Irreversible Covalent Inhibitors of Plasmodium falciparum Serine Protease PfSUB1

Abstract Malaria, caused by Plasmodium parasites, remains a major global health challenge, exacerbated by the widespread emergence of drug-resistant plasmodium strains. Subtilisin-like serine protease SUB1 triggers escape of the parasite from the red cell via a process called egress, rendering the enzyme a prospective antimalarial drug target. While several SUB1 inhibitors have been developed, irreversible covalent inhibition has not been explored so far. In this work, we report our studies of peptidic inhibitors bearing covalent serine traps such as β-lactam, β-lactone, epoxide, and diaryl phosphonate. Out of these, peptidic diaryl phosphonates were found to be irreversible PfSUB1 inhibitors, with the best inhibitor 3b showing a PfSUB1 inhibitory potency (IC50) of 167 nM.