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Cited by 3Malaria Research and ControlOrganophosphorus compounds synthesisPhytochemical compounds biological activities

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Mixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets

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Bennett, John M., Narwal, Sunil K., Kabeche, Stephanie, Abegg, Daniel, Thathy, Vandana, Hackett, Fiona, Yeo, Tomas, Li, Veronica L., Muir, Ryan, Faucher, Franco, Lovell, Scott, Blackman, Michael J., Adibekian, Alexander, Yeh, Ellen, Fidock, David A., Bogyo, Matthew·2024·Cell Chemical Biology
DOI 10.1016/j.chembiol.2024.07.006PMC PMC11457795

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Abstract

Malaria, caused by Plasmodium falciparum, remains a significant health burden. One major barrier for developing antimalarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism that results in a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a small library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent antiparasitic potencies that enabled the identification of therapeutically relevant targets. The active compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor orlistat and shows synergistic killing with orlistat. 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 promising, synthetically tractable antimalarials.

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Research works printed but not linked: 65

  1. Rosenthal, 2019, Malaria: How Are We Doing and How Can We Do Better?, Am. J. Trop. Med. Hyg., 100, 239, 10.4269/ajtmh.18-0997 · DOI
  2. Ashley, 2014, Spread of Artemisinin Resistance in Plasmodium falciparum Malaria, N. Engl. J. Med., 371, 411, 10.1056/NEJMoa1314981 · DOI · Paper page
  3. Balikagala, 2021, Evidence of Artemisinin-Resistant Malaria in Africa, N. Engl. J. Med., 385, 1163, 10.1056/NEJMoa2101746 · DOI
  4. Noedl, 2009, Artemisinin-Resistant Malaria in Asia, N. Engl. J. Med., 361, 540, 10.1056/NEJMc0900231 · DOI
  5. Small-Saunders, 2022, Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance, PLoS Pathog., 18, 10.1371/journal.ppat.1010278 · DOI
  6. Straimer, 2015, K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates, Science, 347, 428, 10.1126/science.1260867 · DOI
  7. Spilling, 2019, The Chemistry and Biology of Cyclophostin, the Cyclipostins and Related Compounds, Molecules, 24, 2579, 10.3390/molecules24142579 · DOI
  8. Madani, 2019, Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of Mycobacterium abscessus, ACS Infect. Dis., 5, 1597, 10.1021/acsinfecdis.9b00172 · DOI
  9. Nguyen, 2017, Cyclipostins and Cyclophostin analogs as promising compounds in the fight against tuberculosis, Sci. Rep., 7, 10.1038/s41598-017-11843-4 · DOI
  10. Schulze, 2015, Salinipostins A–K, Long-Chain Bicyclic Phosphotriesters as a Potent and Selective Antimalarial Chemotype, J. Org. Chem., 80, 1312, 10.1021/jo5024409 · DOI
  11. Yoo, 2020, The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites, Cell Chem. Biol., 27, 143, 10.1016/j.chembiol.2020.01.001 · DOI
  12. Bridgford, 2018, Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome, Nat. Commun., 9, 3801, 10.1038/s41467-018-06221-1 · DOI
  13. Ismail, 2016, Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7, Proc. Natl. Acad. Sci. USA, 113, 2080, 10.1073/pnas.1600459113 · DOI
  14. Ribbiso, 2021, Artemisinin-Based Drugs Target the Plasmodium falciparum Heme Detoxification Pathway, Antimicrob. Agents Chemother., 65, 10.1128/AAC.02137-20 · DOI
  15. Long, 2011, The Metabolic Serine Hydrolases and Their Functions in Mammalian Physiology and Disease, Chem. Rev., 111, 6022, 10.1021/cr200075y · DOI
  16. Bachovchin, 2012, The pharmacological landscape and therapeutic potential of serine hydrolases, Nat. Rev. Drug Discov., 11, 52, 10.1038/nrd3620 · DOI
  17. Tokumasu, 2021, Creative interior design by Plasmodium falciparum: Lipid metabolism and the parasite’s secret chamber, Parasitol. Int., 83, 10.1016/j.parint.2021.102369 · DOI
  18. Déchamps, 2010, Glycerophospholipid acquisition in Plasmodium – A puzzling assembly of biosynthetic pathways, Int. J. Parasitol., 40, 1347, 10.1016/j.ijpara.2010.05.008 · DOI
  19. Déchamps, 2010, Rodent and nonrodent malaria parasites differ in their phospholipid metabolic pathways, J. Lipid Res., 51, 81, 10.1194/jlr.M900166-JLR200 · DOI
  20. Elahi, 2019, Functional annotation of serine hydrolases in the asexual erythrocytic stage of Plasmodium falciparum, Sci. Rep., 9, 10.1038/s41598-019-54009-0 · DOI
  21. Davison, 2022, Activity-based protein profiling of human and plasmodium serine hydrolases and interrogation of potential antimalarial targets, iScience, 25, 10.1016/j.isci.2022.104996 · DOI
  22. Faucher, 2020, Strategies for Tuning the Selectivity of Chemical Probes that Target Serine Hydrolases, Cell Chem. Biol., 27, 937, 10.1016/j.chembiol.2020.07.008 · DOI
  23. Elliott, 2012, The use of phosphate bioisosteres in medicinal chemistry and chemical biology, MedChemComm, 3, 735, 10.1039/c2md20079a · DOI
  24. Jackson, 1998, Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase, J. Med. Chem., 41, 2289, 10.1021/jm970543s · DOI
  25. Senten, 2003, Rapid Parallel Synthesis of Dipeptide Diphenyl Phosphonate Esters as Inhibitors of Dipeptidyl Peptidases, J. Comb. Chem., 5, 336, 10.1021/cc020096o · DOI
  26. Serim, 2013, Tuning activity-based probe selectivity for serine proteases by on-resin ‘click’ construction of peptide diphenyl phosphonates, Org. Biomol. Chem., 11, 5714, 10.1039/c3ob40907d · DOI
  27. Lu, 2021, Chemoproteomics for Plasmodium Parasite Drug Target Discovery, Chembiochem, 22, 2591, 10.1002/cbic.202100155 · DOI
  28. Wang, 2019, Discovery and Evaluation of New Activity-Based Probes for Serine Hydrolases, Chembiochem, 20, 2212, 10.1002/cbic.201900126 · DOI
  29. Adibekian, 2011, Click-generated triazole ureas as ultrapotent in vivo–active serine hydrolase inhibitors, Nat. Chem. Biol., 7, 469, 10.1038/nchembio.579 · DOI
  30. Cognetta, 2015, Selective N-Hydroxyhydantoin Carbamate Inhibitors of Mammalian Serine Hydrolases, Chem. Biol., 22, 928, 10.1016/j.chembiol.2015.05.018 · DOI
  31. Zhao, 2018, Total Synthesis of Marine Cyclic Enol-Phosphotriester Salinipostin Compounds, J. Ocean Univ. China, 17, 683, 10.1007/s11802-018-3540-8 · DOI
  32. Huang, 2018, Direct Aryloxylation/Alkyloxylation of Dialkyl Phosphonates for the Synthesis of Mixed Phosphonates, Angew. Chem. Int. Ed., 57, 6624, 10.1002/anie.201802082 · DOI
  33. Zhang, 2018, Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis, Science, 360, 10.1126/science.aap7847 · DOI
  34. Lou, 2022, Sulfonyl fluorides as targets and substrates in the development of new synthetic methods, Nat. Rev. Chem, 6, 146, 10.1038/s41570-021-00352-8 · DOI
  35. Narayanan, 2015, Sulfonyl fluorides as privileged warheads in chemical biology, Chem. Sci., 6, 2650, 10.1039/C5SC00408J · DOI
  36. Sanz, 2012, P. falciparum In Vitro Killing Rates Allow to Discriminate between Different Antimalarial Mode-of-Action, PLoS One, 7, 10.1371/journal.pone.0030949 · DOI
  37. Haberkant, 2016, Bifunctional Sphingosine for Cell-Based Analysis of Protein-Sphingolipid Interactions, ACS Chem. Biol., 11, 222, 10.1021/acschembio.5b00810 · DOI
  38. Istvan, 2017, Esterase mutation is a mechanism of resistance to antimalarial compounds, Nat. Commun., 8, 10.1038/ncomms14240 · DOI
  39. Mistry, 2021, Pfam: The protein families database in 2021, Nucleic Acids Res., 49, D412, 10.1093/nar/gkaa913 · DOI · Paper page
  40. Sievers, 2011, Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega, Mol. Syst. Biol., 7, 539, 10.1038/msb.2011.75 · DOI
  41. Child, 2013, Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion, Nat. Chem. Biol., 9, 651, 10.1038/nchembio.1315 · DOI
  42. Onguka, 2021, Toxoplasma gondii serine hydrolases regulate parasite lipid mobilization during growth and replication within the host, Cell Chem. Biol., 28, 1501, 10.1016/j.chembiol.2021.05.001 · DOI
  43. Remsberg, 2021, ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth, Nat. Chem. Biol., 17, 856, 10.1038/s41589-021-00785-8 · DOI
  44. Poust, 2014, Understanding the Role of Histidine in the GHSxG Acyltransferase Active Site Motif: Evidence for Histidine Stabilization of the Malonyl-Enzyme Intermediate, PLoS One, 9, 10.1371/journal.pone.0109421 · DOI
  45. Pieperhoff, 2015, Conditional U1 Gene Silencing in Toxoplasma gondii, PLoS One, 10, 10.1371/journal.pone.0130356 · DOI
  46. Ganesan, 2016, Synthetic RNA–protein modules integrated with native translation mechanisms to control gene expression in malaria parasites, Nat. Commun., 7, 10.1038/ncomms10727 · DOI
  47. Mi-Ichi, 2007, Oleic acid is indispensable for intraerythrocytic proliferation of Plasmodium falciparum, Parasitology, 134, 1671, 10.1017/S0031182007003137 · DOI
  48. Asad, 2021, An essential vesicular-trafficking phospholipase mediates neutral lipid synthesis and contributes to hemozoin formation in Plasmodium falciparum, BMC Biol., 19, 159, 10.1186/s12915-021-01042-z · DOI
  49. Gulati, 2015, Profiling the Essential Nature of Lipid Metabolism in Asexual Blood and Gametocyte Stages of Plasmodium falciparum, Cell Host Microbe, 18, 371, 10.1016/j.chom.2015.08.003 · DOI
  50. Kümpornsin, 2023, Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum, Nat. Commun., 14, 3059, 10.1038/s41467-023-38774-1 · DOI
  51. Duffey, 2021, Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials, Trends Parasitol., 37, 709, 10.1016/j.pt.2021.04.006 · DOI
  52. Miliara, 2019, Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins, Nat. Commun., 10, 1130, 10.1038/s41467-019-09089-x · DOI
  53. Jeffers, 2017, TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite Toxoplasma gondii, mSphere, 2, 10.1128/mSphere.00229-16 · DOI
  54. Kim, 2021, Structural Insights into Transporter-Mediated Drug Resistance in Infectious Diseases, J. Mol. Biol., 433, 10.1016/j.jmb.2021.167005 · DOI
  55. Bakker, 2023, Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA, J. Am. Chem. Soc., 145, 1136, 10.1021/jacs.2c10819 · DOI
  56. Babin, 2022, Identification of covalent inhibitors that disrupt M. tuberculosis growth by targeting multiple serine hydrolases involved in lipid metabolism, Cell Chem. Biol., 29, 897, 10.1016/j.chembiol.2021.08.013 · DOI
  57. Li, 2022, Identification of cell wall synthesis inhibitors active against Mycobacterium tuberculosis by competitive activity-based protein profiling, Cell Chem. Biol., 29, 883, 10.1016/j.chembiol.2021.09.002 · DOI
  58. Lentz, 2018, Identification of a S. aureus virulence factor by activity-based protein profiling (ABPP), Nat. Chem. Biol., 14, 609, 10.1038/s41589-018-0060-1 · DOI
  59. Straimer, 2017, Plasmodium falciparum K13 Mutations Differentially Impact Ozonide Susceptibility and Parasite Fitness In Vitro, mBio, 8, 10.1128/mBio.00172-17 · DOI
  60. Linares, 2015, Identifying rapidly parasiticidal anti-malarial drugs using a simple and reliable in vitro parasite viability fast assay, Malar. J., 14, 441, 10.1186/s12936-015-0962-2 · DOI
  61. Brunner, 2022, Ultra-high sensitivity mass spectrometry quantifies single-cell proteome changes upon perturbation, Mol. Syst. Biol., 18, 10.15252/msb.202110798 · DOI · Paper page
  62. Cox, 2014, Accurate Proteome-wide Label-free Quantification by Delayed Normalization and Maximal Peptide Ratio Extraction, Termed MaxLFQ, Mol. Cell. Proteomics, 13, 2513, 10.1074/mcp.M113.031591 · DOI · Paper page
  63. Conroy, 2024, LIPID MAPS: update to databases and tools for the lipidomics community, Nucleic Acids Res., 52, D1677, 10.1093/nar/gkad896 · DOI
  64. Murithi, 2021, The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance, Sci. Transl. Med., 13, 10.1126/scitranslmed.abg6013 · DOI
  65. Nasamu, 2021, An integrated platform for genome engineering and gene expression perturbation in Plasmodium falciparum, Sci. Rep., 11, 342, 10.1038/s41598-020-77644-4 · DOI

Metadata

Authors
Bennett, J. M., Narwal, S. K., Kabeche, S., Abegg, D., Thathy, V., Hackett, F., Yeo, T., Li, V. L., Muir, R., Faucher, F., Lovell, S., Blackman, M. J., Adibekian, A., Yeh, E., Fidock, D. A., & Bogyo, M.
Affiliations
  • Stanford University (US)
  • Columbia University Irving Medical Center (US)
  • Stanford Medicine (US)
  • University of Illinois Chicago (US)
  • The Francis Crick Institute (GB)
Corresponding author
Bogyo, Matthew
ORCID
Venue
Cell Chemical Biology
Publisher
Elsevier BV
Published
2024-09
Volume
31
Issue
9
Pages
1714-1728.e10
ISSN
  • 2451-9448 (ISSN-L)
  • 2451-9456
DOI
10.1016/j.chembiol.2024.07.006
PMC
PMC11457795
OpenAlex
W4401512694
Cited by
3
References
3
Citations by year
2025: 3
FWCI
1.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell chemical biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • Figshare (submittedVersion, cc-by)
  • The Francis Crick Institute (cc-by)
Funders
  • Bill and Melinda Gates Foundation (INV-033538)
  • U.S. Department of Defense (T32 GM113854, W81XWII2210520, W81XWH2210520)
  • Wellcome Trust (220318/A/20/Z)
  • National Institutes of Health (R01 AI109023, T32 GM113854, R33 AI127581, R33 AH27581)
  • Francis Crick Institute
  • Cancer Research UK
  • UKRI Medical Research Council (CC2129)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Physical Sciences › Chemistry › Organic Chemistry › Organophosphorus compounds synthesis
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Phytochemical compounds biological activities
Keywords
antimalarial drug discovery, Plasmodium falciparum, serine hydrolases, lipid metabolism, bioisosteres, orlistat, multidrug resistance, drug resistance, synergistic drug combination, natural product derivatives

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