biostudies-literatureSundararaman SAIndiana Academy of Science (IAS)Pediatric Infectious Diseases Society (PIDS)NIAID NIH HHSChildren's Hospital of Philadelphia (CHOP)Doris Duke Charitable Foundation (DDCF)HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)e2417682122https://www.ebi.ac.uk/biostudies/studies/S-EPMC11912422biostudies-literatureUnknown122(10)The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by undesirable drug-like properties of lead compounds. Prodrug approaches temporarily mask undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin (Fsm), exhibit significantly higher antimalarial potency than their parent compounds [R.L. Edwards <i>et al.</i>, <i>Sci. Rep.</i> <b>7</b>, 8400 (2017)]. However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH), is the major activating enzyme of multiple lipophilic ester prodrugProceedings of the National Academy of Sciences of the United States of AmericaProdrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH).PMC11912422Paragon of Research Excellence AwardR01AI171514Senior Research GrantPIDS-St. Jude Children's Research Hospital Fellowship Award in Basic and Translational ScienceT32 AI141393R01 AI171514T32 AI118684T32AI118684K-Readiness Pilot GrantR01AI123433T32AI141393R01 AI123433R01 AI103280R01AI103280Hoops GCDaley ECApple GADaniels AMRouamba RWBague DAHeidel KMJohnson RJKasak PDurand AJEdwards RLKourtoglou ECEsteb JJOdom John ARSundararaman SADowd CSO'Brien KAWilson MAWhite ADMiller JJAugust SAKoelper AJMuller FLfalseProdrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH).The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by undesirable drug-like properties of lead compounds. Prodrug approaches temporarily mask undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin (Fsm), exhibit significantly higher antimalarial potency than their parent compounds [R.L. Edwards <i>et al.</i>, <i>Sci. Rep.</i> <b>7</b>, 8400 (2017)]. However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH), is the major activating enzyme of multiple lipophilic ester prodrug2025-01-01T00:00:00Z2025 Mar2026-07-15T05:56:47.298Z2026-06-30T03:21:57.682ZS-EPMC119124224003575510.1073/pnas.2417682122