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Allosteric inhibition of tRNA synthetase Gln4 by N-pyrimidinyl-ß-thiophenylacrylamides exerts highly selective antifungal activity.
Puumala, Emily; Sychantha, David; Lach, Elizabeth; Reeves, Shawn; Nabeela, Sunna; Fogal, Meea; Nigam, AkshatKumar; Johnson, Jarrod W; Aspuru-Guzik, Alán; Shapiro, Rebecca S; Uppuluri, Priya; Kalyaanamoorthy, Subha; Magolan, Jakob; Whitesell, Luke; Robbins, Nicole; Wright, Gerard D; Cowen, Leah E.
Afiliação
  • Puumala E; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Sychantha D; M.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.
  • Lach E; M.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.
  • Reeves S; Department of Chemistry, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
  • Nabeela S; Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, Torrance, CA 90502, USA.
  • Fogal M; Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
  • Nigam A; Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
  • Johnson JW; M.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.
  • Aspuru-Guzik A; Chemical 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, Canad
  • Shapiro RS; Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
  • Uppuluri P; Division 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.
  • Kalyaanamoorthy S; Department of Chemistry, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
  • Magolan J; M.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.
  • Whitesell L; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Robbins N; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Wright GD; M.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.
  • Cowen LE; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: leah.cowen@utoronto.ca.
Cell Chem Biol ; 31(4): 760-775.e17, 2024 Apr 18.
Article em En | MEDLINE | ID: mdl-38402621
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-ß-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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Aminoacil-tRNA Sintetases / Antifúngicos Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Aminoacil-tRNA Sintetases / Antifúngicos Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article