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

  • Cell Chem Biol. 2024 Apr 18;31(4):760-775.e17. doi: 10.1016/j.chembiol.2024.01.010.
Emily Puumala  1 ,  David Sychantha  2 ,  Elizabeth Lach  2 ,  Shawn Reeves  3 ,  Sunna Nabeela  4 ,  Meea Fogal  5 ,  AkshatKumar Nigam  6 ,  Jarrod W Johnson  2 ,  Alán Aspuru-Guzik  7 ,  Rebecca S Shapiro  5 ,  Priya Uppuluri  8 ,  Subha Kalyaanamoorthy  3 ,  Jakob Magolan  2 ,  Luke Whitesell  1 ,  Nicole Robbins  1 ,  Gerard D Wright  2 ,  Leah E Cowen  9
Affiliations
  • 1. Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 2. 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.
  • 3. Department of Chemistry, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
  • 4. Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, Torrance, CA 90502, USA.
  • 5. Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
  • 6. Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
  • 7. 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, 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.
  • 8. 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.
  • 9. Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].
PMID: 38402621 DOI: 10.1016/j.chembiol.2024.01.010
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.

Keywords
Candida; Gln4; antifungal; fungal pathogens; glutaminyl-tRNA synthetase; translation inhibitor.
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