{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T10:00:28Z","timestamp":1784800828992,"version":"3.55.0"},"posted":{"date-parts":[[2026,5,15]]},"group-title":"Biochemistry","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Malaria remains one of the major threats to human health. Breakthrough drugs with high potency and low resistance risk are needed to combat the ever-increasing resistance to currently deployed antimalarials. Here, we explore a series of 4-amino-quinazoline-based sulfonamides, with drug-like physicochemical parameters and a synthetically accessible scaffold. Exemplars exhibit nanomolar potency against blood stage\n                  <jats:italic>Plasmodium<\/jats:italic>\n                  cultures, with up to 300-fold selectivity compared with a mammalian cell line. The compounds are also active against transmissible stages of\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  and are refractory to resistance development. Targeted mass spectrometry reveals that the compounds act as reaction hijacking inhibitors targeting\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  aminoacyl tRNA synthetases (aaRSs). Subtle changes to the chemical structure switch the main target from cytoplasmic tRNA threonine synthetase (\n                  <jats:italic>Pf<\/jats:italic>\n                  ThrRS) to cytoplasmic asparagine synthetase (\n                  <jats:italic>Pf<\/jats:italic>\n                  AsnRS), a change that is associated with increased potency and selectivity. The target preference was confirmed by selective knock-down of different\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  aaRSs and by tolerance selection in a mutator line. Consistent with aaRS targets, exemplar compounds activate the amino acid starvation response. Recombinant enzyme inhibition and thermal stabilisation assays confirm the susceptibility of\n                  <jats:italic>Pf<\/jats:italic>\n                  AsnRS to reaction hijacking and show that human AsnRS is less susceptible. A molecular model of Asn-tRNA-bound\n                  <jats:italic>Pf<\/jats:italic>\n                  AsnRS reveals that a potent hijacker adopts a pose similar to adenosine 5\u2019-monophosphate (AMP). An AlphaFold model of the native\n                  <jats:italic>Pf<\/jats:italic>\n                  AsnRS dimer helps explain the tolerance-conferring effect of a mutation at the dimer interface.\n                <\/jats:p>","DOI":"10.64898\/2026.05.15.725388","type":"posted-content","created":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T04:00:15Z","timestamp":1778904015000},"source":"Crossref","is-referenced-by-count":0,"title":["Potent reaction hijacking inhibitors of\n                  <i>Plasmodium falciparum<\/i>\n                  asparagine tRNA synthetase"],"prefix":"10.64898","author":[{"given":"Xi","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisl Y.","family":"Esherick","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nutpakal","family":"Ketprasit","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil K.","family":"Narwal","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz C.","family":"Godoy","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nonlawat","family":"Boonyalai","sequence":"additional","affiliation":[{"name":"Biological Chemistry and Drug Discovery, Faculty of Life Sciences, University of Dundee, Dundee DD1 4HN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Con","family":"Dogovski","sequence":"additional","affiliation":[{"name":"Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig J.","family":"Morton","sequence":"additional","affiliation":[{"name":"Biotherapeutics Program CSIRO, Clayton South, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tayla","family":"Rabie","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mufuliat Toyin","family":"Famodimu","sequence":"additional","affiliation":[{"name":"London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Wei","family":"Tai","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Yeo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena H. M.","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Leeming","sequence":"additional","affiliation":[{"name":"Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Laureano De Souza","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Chenu","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture, 20, Route de Pr\u00e9-Bois, 1215, Geneva 15, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7497-7082","authenticated-orcid":false,"given":"Darren J.","family":"Creek","sequence":"additional","affiliation":[{"name":"Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Delves","sequence":"additional","affiliation":[{"name":"London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyn-Marie","family":"Birkholtz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa"},{"name":"Department of Biochemistry, Stellenbosch University, Stellenbosch, 7600, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Duffy","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture, 20, Route de Pr\u00e9-Bois, 1215, Geneva 15, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Lobb","sequence":"additional","affiliation":[{"name":"Lgenia, Inc., 412 S Maple St, Fortville, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Durst","sequence":"additional","affiliation":[{"name":"Lgenia, Inc., 412 S Maple St, Fortville, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4973-0915","authenticated-orcid":false,"given":"Marcus C.S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Biological Chemistry and Drug Discovery, Faculty of Life Sciences, University of Dundee, Dundee DD1 4HN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Fidock","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA"},{"name":"Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquin C.","family":"Niles","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miles G.","family":"Siegel","sequence":"additional","affiliation":[{"name":"Lgenia, Inc., 412 S Maple St, Fortville, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9910-0199","authenticated-orcid":false,"given":"Leann","family":"Tilley","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley C.","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia"},{"name":"Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072302000465000_2026.05.15.725388v2.1","unstructured":"World_Health_Organisation. 2025. 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