{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T15:09:47Z","timestamp":1790262587513,"version":"4.1.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"9","license":[{"start":{"date-parts":[[2018,8,12]],"date-time":"2018-08-12T00:00:00Z","timestamp":1534032000000},"content-version":"vor","delay-in-days":181,"URL":"http:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["GM041916"],"award-info":[{"award-number":["GM041916"]}],"id":[{"id":"10.13039\/100000002","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":[[2018,2,27]]},"abstract":"<jats:p>\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    causes the most lethal form of human malaria and is a global health concern. The parasite responds to antimalarial therapies by developing drug resistance. The continuous development of new antimalarials with novel mechanisms of action is a priority for drug combination therapies. The use of transition-state analog inhibitors to block essential steps in purine salvage has been proposed as a new antimalarial approach. Mutations that reduce transition-state analog binding are also expected to reduce the essential catalytic function of the target. We have previously reported that inhibition of host and\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    purine nucleoside phosphorylase (\n                    <jats:italic>Pf<\/jats:italic>\n                    PNP) by DADMe-Immucillin-G (DADMe-ImmG) causes purine starvation and parasite death in vitro and in primate infection models.\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    cultured under incremental DADMe-ImmG drug pressure initially exhibited increased\n                    <jats:italic>Pf<\/jats:italic>\n                    PNP gene copy number and protein expression. At increased drug pressure, additional\n                    <jats:italic>Pf<\/jats:italic>\n                    PNP gene copies appeared with point mutations at catalytic site residues involved in drug binding. Mutant\n                    <jats:italic>Pf<\/jats:italic>\n                    PNPs from resistant clones demonstrated reduced affinity for DADMe-ImmG, but also reduced catalytic efficiency. The catalytic defects were partially overcome by gene amplification in the region expressing\n                    <jats:italic>Pf<\/jats:italic>\n                    PNP. Crystal structures of native and mutated\n                    <jats:italic>Pf<\/jats:italic>\n                    PNPs demonstrate altered catalytic site contacts to DADMe-ImmG. Both point mutations and gene amplification are required to overcome purine starvation induced by DADMe-ImmG. Resistance developed slowly, over 136 generations (2\n                    <jats:sup>136<\/jats:sup>\n                    clonal selection). Transition-state analog inhibitors against\n                    <jats:italic>Pf<\/jats:italic>\n                    PNP are slow to induce resistance and may have promise in malaria therapy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1525670115","type":"journal-article","created":{"date-parts":[[2018,2,12]],"date-time":"2018-02-12T15:25:17Z","timestamp":1518449117000},"page":"2114-2119","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":29,"title":["Genetic resistance to purine nucleoside phosphorylase inhibition in\n                    <i>Plasmodium falciparum<\/i>"],"prefix":"10.1073","volume":"115","author":[{"given":"Rodrigo G.","family":"Ducati","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilda A.","family":"Namanja-Magliano","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh K.","family":"Harijan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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Lancet Infect Dis 7, 93\u2013104 (2007).","journal-title":"Lancet Infect Dis"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/S0035-9203(03)90012-5","article-title":"Importance and prevention of malaria in pregnancy","volume":"97","author":"Shulman CE","year":"2003","unstructured":"CE Shulman, EK Dorman, Importance and prevention of malaria in pregnancy. Trans R Soc Trop Med Hyg 97, 30\u201335 (2003).","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"e_1_3_4_3_2","volume-title":"World Malaria Report 2016","author":"WHO","year":"2016","unstructured":"; WHO World Malaria Report 2016 (WHO, Geneva, 2016)."},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1126\/science.1155165","article-title":"Qinghaosu (artemisinin): The price of success","volume":"320","author":"White NJ","year":"2008","unstructured":"NJ White, Qinghaosu (artemisinin): The price of success. 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J Biol Chem 277, 3226\u20133231 (2002).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"18103","DOI":"10.1074\/jbc.C400068200","article-title":"Plasmodium falciparum purine nucleoside phosphorylase: Crystal structures, immucillin inhibitors, and dual catalytic function","volume":"279","author":"Shi W","year":"2004","unstructured":"W Shi, , Plasmodium falciparum purine nucleoside phosphorylase: Crystal structures, immucillin inhibitors, and dual catalytic function. J Biol Chem 279, 18103\u201318106 (2004).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/0166-6851(82)90035-4","article-title":"Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum","volume":"5","author":"Reyes P","year":"1982","unstructured":"P Reyes, , Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum. Mol Biochem Parasitol 5, 275\u2013290 (1982).","journal-title":"Mol Biochem Parasitol"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1101\/gr.2523904","article-title":"Global analysis of transcript and protein levels across the Plasmodium falciparum life cycle","volume":"14","author":"Le Roch KG","year":"2004","unstructured":"KG Le Roch, , Global analysis of transcript and protein levels across the Plasmodium falciparum life cycle. Genome Res 14, 2308\u20132318 (2004).","journal-title":"Genome Res"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1550-7408.1985.tb03013.x","article-title":"Nutritional requirements of Plasmodium falciparum in culture. I. Exogenously supplied dialyzable components necessary for continuous growth","volume":"32","author":"Divo AA","year":"1985","unstructured":"AA Divo, TG Geary, NL Davis, JB Jensen, Nutritional requirements of Plasmodium falciparum in culture. I. Exogenously supplied dialyzable components necessary for continuous growth. J Protozool 32, 59\u201364 (1985).","journal-title":"J Protozool"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1146\/annurev.bb.05.060176.001415","article-title":"Transition state analog inhibitors and enzyme catalysis","volume":"5","author":"Wolfenden R","year":"1976","unstructured":"R Wolfenden, Transition state analog inhibitors and enzyme catalysis. Annu Rev Biophys Bioeng 5, 271\u2013306 (1976).","journal-title":"Annu Rev Biophys Bioeng"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.ddtec.2014.03.002","article-title":"Antimalarial drug resistance: New treatments options for Plasmodium","volume":"11","author":"Gamo FJ","year":"2014","unstructured":"FJ Gamo, Antimalarial drug resistance: New treatments options for Plasmodium. 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Malar J 12, 377 (2013).","journal-title":"Malar J"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1186\/s13059-014-0511-2","article-title":"A genomic and evolutionary approach reveals non-genetic drug resistance in malaria","volume":"15","author":"Herman JD","year":"2014","unstructured":"JD Herman, , A genomic and evolutionary approach reveals non-genetic drug resistance in malaria. Genome Biol 15, 511 (2014).","journal-title":"Genome Biol"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1186\/s13059-014-0544-6","article-title":"Drug resistance genomics of the antimalarial drug artemisinin","volume":"15","author":"Winzeler EA","year":"2014","unstructured":"EA Winzeler, MJ Manary, Drug resistance genomics of the antimalarial drug artemisinin. 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PLoS Genet 9, e1003293 (2013).","journal-title":"PLoS Genet"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"3908","DOI":"10.1128\/AAC.01793-10","article-title":"Piperaquine resistance is associated with a copy number variation on chromosome 5 in drug-pressured Plasmodium falciparum parasites","volume":"55","author":"Eastman RT","year":"2011","unstructured":"RT Eastman, NV Dharia, EA Winzeler, DA Fidock, Piperaquine resistance is associated with a copy number variation on chromosome 5 in drug-pressured Plasmodium falciparum parasites. Antimicrob Agents Chemother 55, 3908\u20133916 (2011).","journal-title":"Antimicrob Agents Chemother"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"2934","DOI":"10.1128\/AAC.05163-14","article-title":"Decreasing pfmdr1 copy number suggests that Plasmodium falciparum in Western Cambodia is regaining in vitro susceptibility to mefloquine","volume":"59","author":"Lim P","year":"2015","unstructured":"P Lim, , Decreasing pfmdr1 copy number suggests that Plasmodium falciparum in Western Cambodia is regaining in vitro susceptibility to mefloquine. Antimicrob Agents Chemother 59, 2934\u20132937 (2015).","journal-title":"Antimicrob Agents Chemother"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1093\/jac\/dkp449","article-title":"In vitro selection of Plasmodium falciparum drug-resistant parasite lines","volume":"65","author":"Nzila A","year":"2010","unstructured":"A Nzila, L Mwai, In vitro selection of Plasmodium falciparum drug-resistant parasite lines. J Antimicrob Chemother 65, 390\u2013398 (2010).","journal-title":"J Antimicrob Chemother"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"e31623","DOI":"10.1371\/journal.pone.0031623","article-title":"Genome wide adaptations of Plasmodium falciparum in response to lumefantrine selective drug pressure","volume":"7","author":"Mwai L","year":"2012","unstructured":"L Mwai, , Genome wide adaptations of Plasmodium falciparum in response to lumefantrine selective drug pressure. PLoS One 7, e31623 (2012).","journal-title":"PLoS One"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/j.1365-2958.2012.08180.x","article-title":"Mechanisms of in vitro resistance to dihydroartemisinin in Plasmodium falciparum","volume":"86","author":"Cui L","year":"2012","unstructured":"L Cui, , Mechanisms of in vitro resistance to dihydroartemisinin in Plasmodium falciparum. Mol Microbiol 86, 111\u2013128 (2012).","journal-title":"Mol Microbiol"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF00928361","article-title":"Physiological concentrations of purines and pyrimidines","volume":"140","author":"Traut TW","year":"1994","unstructured":"TW Traut, Physiological concentrations of purines and pyrimidines. Mol Cell Biochem 140, 1\u201322 (1994).","journal-title":"Mol Cell Biochem"},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1126\/science.7015505","article-title":"Cloning of naturally occurring mixed infections of malaria parasites","volume":"212","author":"Rosario V","year":"1981","unstructured":"V Rosario, Cloning of naturally occurring mixed infections of malaria parasites. Science 212, 1037\u20131038 (1981).","journal-title":"Science"},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"15907","DOI":"10.1074\/jbc.M117.801779","article-title":"Intracellular rebinding of transition-state analogues provides extended in vivo inhibition lifetimes on human purine nucleoside phosphorylase","volume":"292","author":"Gebre ST","year":"2017","unstructured":"ST Gebre, SA Cameron, L Li, YS Babu, VL Schramm, Intracellular rebinding of transition-state analogues provides extended in vivo inhibition lifetimes on human purine nucleoside phosphorylase. J Biol Chem 292, 15907\u201315915 (2017).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"31465","DOI":"10.1074\/jbc.C300259200","article-title":"Achieving the ultimate physiological goal in transition state analogue inhibitors for purine nucleoside phosphorylase","volume":"278","author":"Lewandowicz A","year":"2003","unstructured":"A Lewandowicz, PC Tyler, GB Evans, RH Furneaux, VL Schramm, Achieving the ultimate physiological goal in transition state analogue inhibitors for purine nucleoside phosphorylase. J Biol Chem 278, 31465\u201331468 (2003).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1107\/S0907444905020251","article-title":"Structures of Plasmodium falciparum purine nucleoside phosphorylase complexed with sulfate and its natural substrate inosine","volume":"61","author":"Schnick C","year":"2005","unstructured":"C Schnick, , Structures of Plasmodium falciparum purine nucleoside phosphorylase complexed with sulfate and its natural substrate inosine. Acta Crystallogr D Biol Crystallogr 61, 1245\u20131254 (2005).","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"e84384","DOI":"10.1371\/journal.pone.0084384","article-title":"Structural determinants of the 5\u2032-methylthioinosine specificity of Plasmodium purine nucleoside phosphorylase","volume":"9","author":"Donaldson TM","year":"2014","unstructured":"TM Donaldson, , Structural determinants of the 5\u2032-methylthioinosine specificity of Plasmodium purine nucleoside phosphorylase. PLoS One 9, e84384 (2014).","journal-title":"PLoS One"},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"13944","DOI":"10.1073\/pnas.94.25.13944","article-title":"Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum","volume":"94","author":"Triglia T","year":"1997","unstructured":"T Triglia, JG Menting, C Wilson, AF Cowman, Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum. Proc Natl Acad Sci USA 94, 13944\u201313949 (1997).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","first-page":"18883","DOI":"10.1073\/pnas.0911317106","article-title":"Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine","volume":"106","author":"S\u00e1 JM","year":"2009","unstructured":"JM S\u00e1, , Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine. 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