2. Academic Validation
  3. Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

  • Res Sq. 2023 Jul 27:rs.3.rs-3198291. doi: 10.21203/rs.3.rs-3198291/v1.
Stanley C Xie 1,  Yinuo Wang 2,  Craig J Morton 3,  Riley D Metcalfe 4,  Con Dogovski 1,  Charisse Flerida A Pasaje 5,  Elyse Dunn 1,  Madeline R Luth 6,  Krittikorn Kumpornsin 7 8,  Eva S Istvan 9,  Joon Sung Park 10,  Kate J Fairhurst 11 12,  Nutpakal Ketprasit 1,  Tomas Yeo 11 12,  Okan Yildirim 13,  Mathamsanqa N Bhebhe 14,  Dana M Klug 2,  Peter J Rutledge 14,  Luiz C Godoy 5,  Sumanta Dey 5,  Mariana Laureano De Souza 6,  Jair L Siqueira-Neto 6,  Yawei Du 1,  Tanya Puhalovich 1,  Mona Amini 1,  Gerry Shami 1,  Duangkamon Loesbanluechai 7,  Shuai Nie 15,  Nicholas Williamson 15,  Gouranga P Jana 16,  Bikash C Maity 16,  Patrick Thomson 17,  Thomas Foley 17,  Derek S Tan 13,  Jacquin C Niles 5,  Byung Woo Han 10,  Daniel E Goldberg 9,  Jeremy Burrows 18,  David A Fidock 11 12 19,  Marcus C S Lee 7 20,  Elizabeth A Winzeler 6,  Michael D W Griffin 1,  Matthew H Todd 2 21,  Leann Tilley 1
Affiliations

Affiliations

  • 1 Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • 2 School of Pharmacy, University College London, London WC1N 1AX, United Kingdom.
  • 3 Biomedical Manufacturing Program, CSIRO, Clayton South, Australia.
  • 4 Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
  • 5 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 6 Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
  • 7 Parasites and Microbes Programme, Wellcome Sanger Institute, Hinxton, CB10 1SA, United Kingdom.
  • 8 Calibr, Division of the Scripps Research Institute, La Jolla, CA 92037, USA.
  • 9 Division of Infectious Diseases, Department of Medicine, Washington University in St. Louis, USA.
  • 10 Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 11 Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Medical Center, New York, NY 10032, USA.
  • 12 Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
  • 13 Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 14 School of Chemistry, University of Sydney, Camperdown, NSW 2006, Australia.
  • 15 Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • 16 TCG Lifesciences Private Limited, Salt-lake Electronics Complex, Kolkata, India.
  • 17 School of Chemistry, The University of Edinburgh, Edinburgh EH9 3JJ, United Kingdom.
  • 18 Medicines for Malaria Venture, 20, Route de Pré-Bois 1215, Geneva 15, Switzerland.
  • 19 Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
  • 20 Wellcome Centre for Anti-Infectives Research, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, United Kingdom.
  • 21 Structural Genomics Consortium, University College London, London WC1N 1AX, United Kingdom.
PMID: 37546892 DOI: 10.21203/rs.3.rs-3198291/v1
Abstract

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against Parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure activity relationship and the selectivity mechanism.

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