TY - JOUR
T1 - Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase
AU - Xie, Stanley C.
AU - Wang, Yinuo
AU - Morton, Craig J.
AU - Metcalfe, Riley D.
AU - Dogovski, Con
AU - Pasaje, Charisse Flerida A.
AU - Dunn, Elyse
AU - Luth, Madeline R.
AU - Kumpornsin, Krittikorn
AU - Istvan, Eva S.
AU - Park, Joon Sung
AU - Fairhurst, Kate J.
AU - Ketprasit, Nutpakal
AU - Yeo, Tomas
AU - Yildirim, Okan
AU - Bhebhe, Mathamsanqa N.
AU - Klug, Dana M.
AU - Rutledge, Peter J.
AU - Godoy, Luiz C.
AU - Dey, Sumanta
AU - De Souza, Mariana Laureano
AU - Siqueira-Neto, Jair L.
AU - Du, Yawei
AU - Puhalovich, Tanya
AU - Amini, Mona
AU - Shami, Gerry
AU - Loesbanluechai, Duangkamon
AU - Nie, Shuai
AU - Williamson, Nicholas
AU - Jana, Gouranga P.
AU - Maity, Bikash C.
AU - Thomson, Patrick
AU - Foley, Thomas
AU - Tan, Derek S.
AU - Niles, Jacquin C.
AU - Han, Byung Woo
AU - Goldberg, Daniel E.
AU - Burrows, Jeremy
AU - Fidock, David A.
AU - Lee, Marcus C.S.
AU - Winzeler, Elizabeth A.
AU - Griffin, Michael D.W.
AU - Todd, Matthew H.
AU - Tilley, Leann
N1 - Publisher Copyright:
© 2024, The Author(s).
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85183871199&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-45224-z
DO - 10.1038/s41467-024-45224-z
M3 - Article
C2 - 38297033
AN - SCOPUS:85183871199
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 937
ER -