Reaction hijacking inhibition of asparagine tRNA synthetase.

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July 27, 2023
Stanley C Xie SC, Yinuo Wang Y, Craig J Morton CJ, Riley D Metcalfe RD, Con Dogovski C, Charisse Flerida A Pasaje CFA, Elyse Dunn E, Madeline R Luth MR, Krittikorn Kumpornsin K, Eva S Istvan ES, Joon Sung Park JS, Kate J Fairhurst KJ, Nutpakal Ketprasit N, Tomas Yeo T, Okan Yildirim O, Mathamsanqa N Bhebhe MN, Dana M Klug DM, Peter J Rutledge PJ, Luiz C Godoy LC, Sumanta Dey S, Mariana Laureano De Souza ML, Jair L Siqueira-Neto JL, Yawei Du Y, Tanya Puhalovich T, Mona Amini M, Gerry Shami G, Duangkamon Loesbanluechai D, Shuai Nie S, Nicholas Williamson N, Gouranga P Jana GP, Bikash C Maity BC, Patrick Thomson P, Thomas Foley T, Derek S Tan DS, Jacquin C Niles JC, Byung Woo Han BW, Daniel E Goldberg DE, Jeremy Burrows J, David A Fidock DA, Marcus C S Lee MCS, Elizabeth A Winzeler EA, Michael D W Griffin MDW, Matthew H Todd MH, Leann Tilley L

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. evolution of resistance using a slow ramp-up approach pointed to the cytoplasmic asparaginyl tRNA synthetase (AsnRS) 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 AsnRS 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 AsnRS provide insights into the structure activity relationship and the selectivity mechanism.

Courtesy of the U.S. National Library of Medicine