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Mixed Alkyl/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets
Open accessPreprint — published as 10.1016/j.chembiol.2024.07.006 · Paper page
Abstract
Summary: 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.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Bennett, J. M., Narwal, S. K., Kabeche, S., Abegg, D., Hackett, F., Yeo, T., Li, V. L., Muir, R. K., Faucher, F. 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
- openRxiv
- Published
- 2024-01-11
- Volume
- 31
- Issue
- 9
- Pages
- 1714-1728.e10
- ISSN
- 2451-9448 (ISSN-L)
- PMC
- PMC11457795
- OpenAlex
- W4401512694
- Cited by
- 3
- References
- 1
- Citations by year
- 2025: 3
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell chemical biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- U.S. Department of Defense (T32 GM113854, W81XWII2210520, R01 AI109023, W81XWH2210520)
- Bill and Melinda Gates Foundation (INV-033538)
- Wellcome Trust (CC2129, 220318/A/20/Z)
- Francis Crick Institute (CC2129)
- Cancer Research UK (CC2129)
- National Institutes of Health (R33 AH27581, GM113854, AI109023)
- Medical Research Council (CC2129)
- National Cancer Institute (R61CA297953)
- National Institute of General Medical Sciences (T32GM113854, R01GM145886)
- National Institute of Allergy and Infectious Diseases (R33AI127581, R01AI141366, R01AI109023)
- 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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