{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:42:01Z","timestamp":1792089721253,"version":"4.4.0"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"14","license":[{"start":{"date-parts":[[2019,3,20]],"date-time":"2019-03-20T00:00:00Z","timestamp":1553040000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1032548"],"award-info":[{"award-number":["OPP1032548"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["094090"],"award-info":[{"award-number":["094090"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["105021"],"award-info":[{"award-number":["105021"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["100993\/Z\/13\/Z"],"award-info":[{"award-number":["100993\/Z\/13\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"publisher","award":["RD\/08\/2800"],"award-info":[{"award-number":["RD\/08\/2800"]}],"id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R21AI123690"],"award-info":[{"award-number":["R21AI123690"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["HHSN272201200025C"],"award-info":[{"award-number":["HHSN272201200025C"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["HHSN272201700059C"],"award-info":[{"award-number":["HHSN272201700059C"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,4,2]]},"abstract":"<jats:p>\n                    Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    and\n                    <jats:italic>Cryptosporidium parvum<\/jats:italic>\n                    in cell-culture studies. Target deconvolution in\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    has shown that cladosporin inhibits lysyl-tRNA synthetase (\n                    <jats:italic>Pf<\/jats:italic>\n                    KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both\n                    <jats:italic>Pf<\/jats:italic>\n                    KRS1 and\n                    <jats:italic>C. parvum<\/jats:italic>\n                    KRS (\n                    <jats:italic>Cp<\/jats:italic>\n                    KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED\n                    <jats:sub>90<\/jats:sub>\n                    = 1.5 mg\/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between\n                    <jats:italic>Pf<\/jats:italic>\n                    KRS1 and\n                    <jats:italic>Cp<\/jats:italic>\n                    KRS. This series of compounds inhibit\n                    <jats:italic>Cp<\/jats:italic>\n                    KRS and\n                    <jats:italic>C. parvum<\/jats:italic>\n                    and\n                    <jats:italic>Cryptosporidium hominis<\/jats:italic>\n                    in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for\n                    <jats:italic>Pf<\/jats:italic>\n                    KRS1 and\n                    <jats:italic>Cp<\/jats:italic>\n                    KRS vs. (human)\n                    <jats:italic>Hs<\/jats:italic>\n                    KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1814685116","type":"journal-article","created":{"date-parts":[[2019,3,20]],"date-time":"2019-03-20T19:15:30Z","timestamp":1553109330000},"page":"7015-7020","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":148,"title":["Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis"],"prefix":"10.1073","volume":"116","author":[{"given":"Beatriz","family":"Baraga\u00f1a","sequence":"first","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Forte","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Choi","sequence":"additional","affiliation":[{"name":"Seattle Structural Genomics Center for Infectious Disease, Seattle, WA 98109;"},{"name":"Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109;"},{"name":"Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA 98109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Nakazawa Hewitt","sequence":"additional","affiliation":[{"name":"Seattle Structural Genomics Center for Infectious Disease, Seattle, WA 98109;"},{"name":"Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109;"},{"name":"Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA 98109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan A.","family":"Bueren-Calabuig","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6763-7354","authenticated-orcid":false,"given":"Jo\u00e3o Pedro","family":"Pisco","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Peet","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Dranow","sequence":"additional","affiliation":[{"name":"Seattle Structural Genomics Center for Infectious Disease, Seattle, WA 98109;"},{"name":"Beryllium Discovery Corp., Bainbridge Island, WA 98110;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chimed","family":"Jansen","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil R.","family":"Norcross","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumiti","family":"Vinayak","sequence":"additional","affiliation":[{"name":"Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Anderson","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie 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92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Vermont, Burlington, VT 05405;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"O\u2019Neill","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, DD1 5EH Dundee, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2007-2170","authenticated-orcid":false,"given":"Kayode K.","family":"Ojo","sequence":"additional","affiliation":[{"name":"Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109;"},{"name":"Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA 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