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Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase. 2024
Stanley C Xie, and
Yinuo Wang, and
Craig J Morton, and
Riley D Metcalfe, and
Con Dogovski, and
Charisse Flerida A Pasaje, and
Elyse Dunn, and
Madeline R Luth, and
Krittikorn Kumpornsin, and
Eva S Istvan, and
Joon Sung Park, and
Kate J Fairhurst, and
Nutpakal Ketprasit, and
Tomas Yeo, and
Okan Yildirim, and
Mathamsanqa N Bhebhe, and
Dana M Klug, and
Peter J Rutledge, and
Luiz C Godoy, and
Sumanta Dey, and
Mariana Laureano De Souza, and
Jair L Siqueira-Neto, and
Yawei Du, and
Tanya Puhalovich, and
Mona Amini, and
Gerry Shami, and
Duangkamon Loesbanluechai, and
Shuai Nie, and
Nicholas Williamson, and
Gouranga P Jana, and
Bikash C Maity, and
Patrick Thomson, and
Thomas Foley, and
Derek S Tan, and
Jacquin C Niles, and
Byung Woo Han, and
Daniel E Goldberg, and
Jeremy Burrows, and
David A Fidock, and
Marcus C S Lee, and
Elizabeth A Winzeler, and
Michael D W Griffin, and
Matthew H Todd, and
Leann Tilley
Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, 3010, Australia.
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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