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 DeyMariana 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, Leann Tilley

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number937
JournalNature communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024

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