Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

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July 27, 2023
Leann Tilley L, Stanley Xie S, Yinuo Wang Y, Craig Morton C, Riley Metcalfe R, Con Dogovski C, Charisse Flerida Pasaje CF, Elyse Dunn E, Madeline Luth M, Krittikorn Kumpornsin K, Eva Istvan E, Joon Park J, Katie Fairhurst K, Tomas Yeo T, Okan Yildirim O, Mathamsanqa Bhebhe M, Dana Klug D, Peter Rutledge P, Luiz Godoy L, Sumanta Dey S, Mariana De Souza M, Jair Siqueira-Neto J, Nutpakal Ketprasit N, Yawei Du Y, Mona Amini M, Gerald Shami G, Shuai Nie S, Nicholas Williamson N, Gouranga Jana G, Bikash Maity B, Patrick Thomson P, Thomas Foley T, Duangkamon Loesbanluechai D, Tanya Puhalovich T, Derek Tan D, Jacquin Niles J, Byung Woo Han BW, Daniel Goldberg D, Jeremy Burrows J, David Fidock D, Marcus Lee M, Elizabeth Winzeler E, Michael Griffin M, Matthew Todd M

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.

Courtesy of the U.S. National Library of Medicine