Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Xie, Stanley C. and Wang, Yinuo and Morton, Craig J. and Metcalfe, Riley D. and Dogovski, Con and Pasaje, Charisse Flerida A. and Dunn, Elyse and Luth, Madeline R. and Kumpornsin, Krittikorn and Istvan, Eva S. and Park, Joon Sung and Fairhurst, Kate J. and Ketprasit, Nutpakal and Yeo, Tomas and Yildirim, Okan and Bhebhe, Mathamsanqa N. and Klug, Dana M. and Rutledge, Peter J. and Godoy, Luiz C. and Dey, Sumanta and De Souza, Mariana Laureano and Siqueira-Neto, Jair L. and Du, Yawei and Puhalovich, Tanya and Amini, Mona and Shami, Gerry and Loesbanluechai, Duangkamon and Nie, Shuai and Williamson, Nicholas and Jana, Gouranga P. and Maity, Bikash C. and Thomson, Patrick and Foley, Thomas and Tan, Derek S. and Niles, Jacquin C. and Han, Byung Woo and Goldberg, Daniel E. and Burrows, Jeremy and Fidock, David A. and Lee, Marcus C.S. and Winzeler, Elizabeth A. and Griffin, Michael D.W. and Todd, Matthew H. and Tilley, Leann (2024) Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase. Nature Communications, 15 (1). 937. ISSN 2041-1723 (https://doi.org/10.1038/s41467-024-45224-z)

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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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