Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Stanley C. Xie, Yinuo Wang, Craig J. Morton, Riley D. Metcalfe, Con Dogovski, Charisse Flerida A. Pasaje, Elyse Dunn, Madeline R. Luth, Krittikorn Kumpornsin, Eva S. Istvan, Joon Sung Park, Kate J. Fairhurst, Nutpakal Ketprasit, Tomas Yeo, Okan Yildirim, Mathamsanqa N. Bhebhe, Dana M. Klug, Peter J. Rutledge, Luiz C. Godoy, Sumanta Dey, Mariana Laureano De Souza, Jair L. Siqueira-Neto, Yawei Du, Tanya Puhalovich, Mona Amini, Gerry Shami, Duangkamon Loesbanluechai, Shuai Nie, Nicholas Williamson, Gouranga P. Jana, Bikash C. Maity, Patrick Thomson, Thomas Foley, Derek S. Tan, Jacquin C. Niles, Byung Woo Han, Daniel E. Goldberg, Jeremy Burrows, David A. Fidock, Marcus C. S. Lee, Elizabeth A. Winzeler (), Michael D. W. Griffin (), Matthew H. Todd () and Leann Tilley ()
Additional contact information
Stanley C. Xie: The University of Melbourne
Yinuo Wang: University College London
Craig J. Morton: Biomedical Manufacturing Program, CSIRO
Riley D. Metcalfe: Center for Structural Biology, Center for Cancer Research, National Cancer Institute
Con Dogovski: The University of Melbourne
Charisse Flerida A. Pasaje: Massachusetts Institute of Technology
Elyse Dunn: The University of Melbourne
Madeline R. Luth: University of California, San Diego
Krittikorn Kumpornsin: Parasites and Microbes Programme, Wellcome Sanger Institute
Eva S. Istvan: Washington University in St. Louis
Joon Sung Park: Seoul National University
Kate J. Fairhurst: Columbia University Medical Center
Nutpakal Ketprasit: The University of Melbourne
Tomas Yeo: Columbia University Medical Center
Okan Yildirim: Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Mathamsanqa N. Bhebhe: University of Sydney
Dana M. Klug: University College London
Peter J. Rutledge: University of Sydney
Luiz C. Godoy: Massachusetts Institute of Technology
Sumanta Dey: Massachusetts Institute of Technology
Mariana Laureano De Souza: University of California, San Diego
Jair L. Siqueira-Neto: University of California, San Diego
Yawei Du: The University of Melbourne
Tanya Puhalovich: The University of Melbourne
Mona Amini: The University of Melbourne
Gerry Shami: The University of Melbourne
Duangkamon Loesbanluechai: Parasites and Microbes Programme, Wellcome Sanger Institute
Shuai Nie: The University of Melbourne
Nicholas Williamson: The University of Melbourne
Gouranga P. Jana: TCG Lifesciences Private Limited
Bikash C. Maity: TCG Lifesciences Private Limited
Patrick Thomson: The University of Edinburgh
Thomas Foley: The University of Edinburgh
Derek S. Tan: Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Jacquin C. Niles: Massachusetts Institute of Technology
Byung Woo Han: Seoul National University
Daniel E. Goldberg: Washington University in St. Louis
Jeremy Burrows: Medicines for Malaria Venture
David A. Fidock: Columbia University Medical Center
Marcus C. S. Lee: Parasites and Microbes Programme, Wellcome Sanger Institute
Elizabeth A. Winzeler: University of California, San Diego
Michael D. W. Griffin: The University of Melbourne
Matthew H. Todd: University College London
Leann Tilley: The University of Melbourne

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45224-z

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