Evidence map›Paper›PMID 38402621›Full record

ArticleCell chemical biology2024

Allosteric inhibition of tRNA synthetase Gln4 by N-pyrimidinyl-β-thiophenylacrylamides exerts highly selective antifungal activity.

Emily Puumala, David Sychantha, Elizabeth Lach, Shawn Reeves, Sunna Nabeela, Meea Fogal, AkshatKumar Nigam, Jarrod W Johnson, Alán Aspuru-Guzik, Rebecca S Shapiro and 7 more

Open access · hybridAbstract 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 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
1.2field-weighted citation impact, top 24% of its field
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

1 citing paper in PubMed, 5 citations in OpenAlex.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors at 7 institutions in 2 countries.

Emily PuumalaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
David SychanthaM.G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
Elizabeth LachM.G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
Shawn ReevesDepartment of Chemistry, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
Sunna NabeelaDivision of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, Torrance, CA 90502, USA.
Meea FogalDepartment of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
AkshatKumar NigamDepartment of Computer Science, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Jarrod W JohnsonM.G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
Alán Aspuru-GuzikChemical Physics Theory Group, Department of Chemistry, University of Toronto Toronto, ON M5S 3H6, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 2E4, Canada; Department of Chemical Engineering & Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada; Department of Materials Science & Engineering, University of Toronto, Toronto, ON M5S 3E4, Canada; Vector Institute for Artificial Intelligence, Toronto, ON M5G 1M1, Canada; Lebovic Fellow, Canadian Institute for Advanced Research (CIFAR), Toronto, ON M5G 1M1, Canada; Acceleration Consortium, University of Toronto, Toronto, ON M5S 3H6, Canada.
Rebecca S ShapiroDepartment of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
Priya UppuluriDivision of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, Torrance, CA 90502, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90024, USA.
Subha KalyaanamoorthyDepartment of Chemistry, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
Jakob MagolanM.G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
Luke WhitesellDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Nicole RobbinsDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Gerard D WrightM.G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
Leah E CowenDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: leah.cowen@utoronto.ca.
Population Health Research Institute · CAUniversity of Toronto · CAUniversity of Guelph · CAUniversity of Waterloo · CALos Angeles Medical Center · USStanford University · USUCLA Medical Center · US

Funding

Systematic Analysis of Morphogenesis, Commensalism, and Virulence in a Leading Human Fungal PathogenR01AI127375 · NIAID · UNIVERSITY OF TORONTO · PI LEAH Elizabeth Cowen · 2017 to 2026
$5.3M
NIAID NIH HHS R01 AI127375
6 · The paper itself

Abstract

Candida species are among the most prevalent causes of systemic fungal infections, which account for ∼1.5 million annual fatalities. Here, we build on a compound screen that identified the molecule N-pyrimidinyl-β-thiophenylacrylamide (NP-BTA), which strongly inhibits Candida albicans growth. NP-BTA was hypothesized to target C. albicans glutaminyl-tRNA synthetase, Gln4. Here, we confirmed through in vitro amino-acylation assays NP-BTA is a potent inhibitor of Gln4, and we defined how NP-BTA arrests Gln4's transferase activity using co-crystallography. This analysis also uncovered Met496 as a critical residue for the compound's species-selective target engagement and potency. Structure-activity relationship (SAR) studies demonstrated the NP-BTA scaffold is subject to oxidative and non-oxidative metabolism, making it unsuitable for systemic administration. In a mouse dermatomycosis model, however, topical application of the compound provided significant therapeutic benefit. This work expands the repertoire of antifungal protein synthesis target mechanisms and provides a path to develop Gln4 inhibitors.

Indexed as

Amino Acyl-tRNA SynthetasesAntifungal AgentsAnimalsCandida albicansMiceStructure-Activity RelationshipAmino Acyl-tRNA SynthetasesAntifungal AgentsantifungalCandidafungal pathogensGln4glutaminyl-tRNA synthetasetranslation inhibitor

Identifiers

PMID38402621
PMCPMC11031294
OpenAlexW4392039234

What OpenQuestion holds

Textmetadata
LicenceTDM
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.