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The potency of (+)-isomers is greater than the (\u2212)-isomers\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            against\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Plasmodium falciparum<\/jats:named-content>\n            malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. falciparum<\/jats:named-content>\n            chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. falciparum<\/jats:named-content>\n            . To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the\n            <jats:italic>in vitro<\/jats:italic>\n            susceptibility of eight clonal lines of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. falciparum<\/jats:named-content>\n            derived from the 106\/1 strain, each containing a unique\n            <jats:italic>pfcrt<\/jats:italic>\n            allele, to four\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Cinchona<\/jats:named-content>\n            stereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of the\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Cinchona<\/jats:named-content>\n            alkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC\n            <jats:sub>50<\/jats:sub>\n            ratio of (\u2212)\/(+) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K\/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel\/transporter with (\u2212) and (+) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and other\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Cinchona<\/jats:named-content>\n            alkaloids.\n          <\/jats:p>","DOI":"10.1128\/aac.05667-11","type":"journal-article","created":{"date-parts":[[2012,8,7]],"date-time":"2012-08-07T02:49:14Z","timestamp":1344307754000},"page":"5356-5364","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids"],"prefix":"10.1128","volume":"56","author":[{"given":"Carol E.","family":"Griffin","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Old Dominion University, Norfolk, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Hoke","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Old Dominion University, Norfolk, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Upeka","family":"Samarakoon","sequence":"additional","affiliation":[{"name":"Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, South Bend, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhui","family":"Duan","sequence":"additional","affiliation":[{"name":"Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbing","family":"Mu","sequence":"additional","affiliation":[{"name":"Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Ferdig","sequence":"additional","affiliation":[{"name":"Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, South Bend, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Warhurst","sequence":"additional","affiliation":[{"name":"Department of Pathogen Molecular Biology, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland A.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Old Dominion University, Norfolk, Virginia, USA"},{"name":"Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2010.08.011"},{"key":"e_1_3_2_3_2","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/j.1476-5381.1959.tb00928.x","article-title":"Some quantitative uses of drug antagonists","volume":"14","author":"Arunlakshana O","year":"1959","unstructured":"ArunlakshanaO SchildHO. 1959. 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