Mixed Alkyl/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets

• Published in: bioRxiv
• Main Authors: Bennett, John M, Narwal, Sunil K, Kabeche, Stephanie, Abegg, Daniel, Hackett, Fiona, Yeo, Tomas, Li, Veronica L, Muir, Ryan K, Faucher, Franco F, Lovell, Scott, Blackman, Michael J, Adibekian, Alexander, Yeh, Ellen, Fidock, David A, Bogyo, Matthew
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 11.01.2024; Cold Spring Harbor Laboratory
• Edition: 1.1
• Subjects: Antiparasitic agents; Isomers; Malaria; Microbiology; Multidrug resistance; Natural products; Parasite resistance; Parasites; Phosphonates; Plasmodium falciparum; Serine; Plasmodium; serine hydrolases; activity-based probes; Activity-Based Protein Profiling; Drug Resistance; lipid metabolism; Serine Hydrolase
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.01.11.575224

Malaria, caused by remains a significant health burden. A barrier for developing anti-malarial drugs is the ability of the parasite to rapidly generate resistance. We demonstrated that Salinipostin A (SalA), a natural product, kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism with a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent anti-parasitic potencies which enabled identification of therapeutically relevant targets. We also confirm that this compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor, Orlistat. Like SalA, our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl/aryl phosphonates are a promising, synthetically tractable anti-malarials with a low-propensity to induce resistance.