Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Xie, S. et al. (2024) Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase. Nature Communications, 15, 937. (doi: 10.1038/s41467-024-45224-z) (PMID:38297033) (PMCID:PMC10831071)

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.

• Item Type: Articles
• Additional Information: We would like to acknowledge funding from the Australian National Health and Medical Research Council (APP2022075; to L.T.), the Australian Research Council (LP120100552; to M.H.T.), Medicines for Malaria Venture (MMV; to L.T., M.H.T. and D.A.F.), the Wellcome Trust (206194/Z/17/Z; to M.C.S.L.), the Wellcome Sanger Institute (to M.C.S.L.). We acknowledge the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (grant number: 2019R1A2C1090251 and RS-2023-00218543 to B.W.H.) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HP23C0102 to B.W.H.). E.A.W., D.A.F., C.F.A.P., M.R.L., E.S.I., J.S.P., M.L.S., K.J.F., T.Y., D.E.G., M.C.S.L., K.K., L.C.G. and S.D. are members of the Malaria Drug Accelerator and are supported by a grant to EAW from the Bill and Melinda Gates Foundation (OPP1054480). M.R.L. was supported in part by a Ruth L. Kirschstein Institutional National Research Award from the National Institute for General Medical Sciences, T32 GM008666. L.T. was supported by an Australian Research Council Laureate Fellowship.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Loesbanluechai, Ms Duangkamon
• Authors: Xie, S., Wang, Y., Morton, C., Metcalfe, R., Dogovski, C., Flerida Pasaje, C., Dunn, E., Luth, M. R., Kumpornsin, K., Istvan, E., Sung Park, J., Fairhurst, K. J., Ketprasit, N., Yeo, T., Yildirim, O., Bhebhe, M., Klug, D. M., Rutledge, P., Godoy, L. C., Laureano de Souza, M., Siqueira-Neto, J. L., Du, Y., Puhalovich, T., Amini, M., Shami, G., Loesbanluechai, D., Nie, S., Williamson, N., Jana, G. P., Maity, B. C., Thomson, P., Foley, T., Tan, D., Niles, J., Woo Han, B., Goldberg, D., Burrows, J., Fidock, D., Lee, M. C.S., Winzeler, E. A., Griffin, M.D.W., Todd, M., and Tilley, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2024 The Authors
• First Published: First published in Nature Communications 15:937
• Publisher Policy: Reproduced under a Creative Commons License