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

Autor:	Bennett JM; Department of Chemistry, Stanford University, Stanford, CA, USA., Narwal SK; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Medical Center, New York, NY, USA., Kabeche S; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA., Abegg D; Department of Chemistry, University of Illinois Chicago, Chicago, IL, USA., Hackett F; Malaria Biochemistry Laboratory, Francis Crick Institute, London NW1 1AT, UK., Yeo T; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Medical Center, New York, NY, USA., Li VL; Department of Chemistry, Stanford University, Stanford, CA, USA., Muir RK; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Faucher FF; Department of Chemistry, Stanford University, Stanford, CA, USA., Lovell S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Blackman MJ; Malaria Biochemistry Laboratory, Francis Crick Institute, London NW1 1AT, UK.; Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK., Adibekian A; Department of Chemistry, University of Illinois Chicago, Chicago, IL, USA., Yeh E; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA., Fidock DA; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Medical Center, New York, NY, USA.; Division of Infectious Diseases, Columbia University Medical Center, New York, NY 10032 USA., Bogyo M; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 11. Date of Electronic Publication: 2024 Jan 11.
DOI:	10.1101/2024.01.11.575224
Abstrakt:	Malaria, caused by Plasmodium falciparum, 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. Competing Interests: Declaration of interests: The authors declare no competing interests.
Databáze:	MEDLINE
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