Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase
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Published:2024-01-31
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Xie Stanley C.ORCID, Wang YinuoORCID, Morton Craig J.ORCID, Metcalfe Riley D.ORCID, Dogovski Con, Pasaje Charisse Flerida A.ORCID, Dunn ElyseORCID, Luth Madeline R., Kumpornsin Krittikorn, Istvan Eva S.ORCID, Park Joon SungORCID, Fairhurst Kate J., Ketprasit NutpakalORCID, Yeo TomasORCID, Yildirim Okan, Bhebhe Mathamsanqa N.ORCID, Klug Dana M., Rutledge Peter J.ORCID, Godoy Luiz C.ORCID, Dey SumantaORCID, De Souza Mariana LaureanoORCID, Siqueira-Neto Jair L., Du YaweiORCID, Puhalovich TanyaORCID, Amini Mona, Shami GerryORCID, Loesbanluechai Duangkamon, Nie Shuai, Williamson NicholasORCID, Jana Gouranga P., Maity Bikash C., Thomson PatrickORCID, Foley Thomas, Tan Derek S.ORCID, Niles Jacquin C.ORCID, Han Byung WooORCID, Goldberg Daniel E.ORCID, Burrows JeremyORCID, Fidock David A.ORCID, Lee Marcus C. S., Winzeler Elizabeth A., Griffin Michael D. W.ORCID, Todd Matthew H.ORCID, Tilley LeannORCID
Abstract
AbstractMalaria 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.
Funder
Department of Health | National Health and Medical Research Council
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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