Evidence map›Paper›PMID 39137783›Full record

ArticleCell chemical biology2024

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

John M Bennett, Sunil K Narwal, Stephanie Kabeche, Daniel Abegg, Vandana Thathy, Fiona Hackett, Tomas Yeo, Veronica L Li, Ryan Muir, Franco Faucher and 6 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

16 authors.

John M BennettDepartment of Chemistry, Stanford University, Stanford, CA, USA.
Sunil K NarwalDepartment 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.
Stephanie KabecheDepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.
Daniel AbeggDepartment of Chemistry, University of Illinois Chicago, Chicago, IL, USA.
Vandana ThathyDepartment 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.
Fiona HackettMalaria Biochemistry Laboratory, Francis Crick Institute, London NW1 1AT, UK.
Tomas YeoDepartment 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.
Veronica L LiDepartment of Chemistry, Stanford University, Stanford, CA, USA.
Ryan MuirDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Franco FaucherDepartment of Chemistry, Stanford University, Stanford, CA, USA.
Scott LovellDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Michael J BlackmanMalaria Biochemistry Laboratory, Francis Crick Institute, London NW1 1AT, UK; Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.
Alexander AdibekianDepartment of Chemistry, University of Illinois Chicago, Chicago, IL, USA.
Ellen YehDepartment 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.
David A FidockDepartment 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.
Matthew BogyoDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: mbogyo@stanford.edu.

Funding

Defining P. falciparum resistance to artemisinin-based combination therapiesR01AI109023 · NIAID · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI FIDOCK, DAVID A · 2014 to 2025
$4.4M
Harnessing the Unique Biogenesis of the Apicomplexan plastid organelle forAntimalarial TargetsR01AI141366 · NIAID · STANFORD UNIVERSITY · PI YEH, ELLEN · 2019 to 2023
$2.9M
Probing conformational changes by protein surface azidationR01GM145886 · NIGMS · UNIVERSITY OF ILLINOIS AT CHICAGO · PI ADIBEKIAN, ALEXANDER · 2022 to 2025
$1.6M
Parasite-specific proteasome inhibitors to combat multi-drug resistant malariaR33AI127581 · NIAID · STANFORD UNIVERSITY · PI BOGYO, MATTHEW · 2019 to 2021
$1.4M
Molecular Pharmacology Training GrantT32GM113854 · NIGMS · STANFORD UNIVERSITY · PI MOCHLY-ROSEN, DARIA · 2015 to 2019
$1.1M
NIAID NIH HHS R01 AI109023NIAID NIH HHS R01 AI141366NIAID NIH HHS R33 AI127581NIGMS NIH HHS R01 GM145886NIGMS NIH HHS T32 GM113854Wellcome Trust CC2129
6 · The paper itself

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.

Indexed as

AntimalarialsOrganophosphonatesPlasmodium falciparumHumansMolecular StructureParasitic Sensitivity TestsStructure-Activity RelationshipAntimalarialsOrganophosphonatesactivity-based probesalky/aryl phosphonatescovalent probesdrug resistancelipid metabolismPlasmodium falciparumserine hydrolases

Identifiers

PMID39137783
PMCPMC11457795

What OpenQuestion holds

Textmetadata
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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.