title: Optimization of plasmepsin inhibitor by focusing on similar structural feature with chloroquine to avoid drug-resistant mechanism of Plasmodium falciparum.
abstract: The plasmepsins are specific aspartic proteases of the malaria parasite and a potential target for developing new antimalarial agents. Our previously reported peptidomimetic plasmepsin inhibitor with modified 2-aminoethylamino substituent, KNI-10740, was tested against chloroquine sensitive Plasmodium falciparum, D6, to be highly potent, however, the inhibitor exhibited about 5 times less activity against multi-drug resistant parasite (TM91C235). We hypothesized the potency reduction resulted from structural similarity between 2-aminoethylamino substituent of KNI-10740 and chloroquine. Then, we modified the moiety and finally identified compound 15d (KNI-10823), that could avoid drug-resistant mechanism of TM91C235 strain.
authors.affiliation: Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Miura
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan.
authors.forename: Koushi
authors.initials: K
authors.lastname: Hidaka
authors.affiliation: Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Azai
authors.affiliation: Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kashimoto
authors.affiliation: Department of Biology and Johns Hopkins Malaria Research Institute, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawasaki
authors.affiliation: Department of Biology and Johns Hopkins Malaria Research Institute, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Shen-En
authors.initials: SE
authors.lastname: Chen
authors.affiliation: Department of Biology and Johns Hopkins Malaria Research Institute, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Renato Ferreira
authors.initials: RF
authors.lastname: de Freitas
authors.affiliation: Department of Biology and Johns Hopkins Malaria Research Institute, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.affiliation: Laboratory of Peptide Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan. Electronic address: y_kiso@nagahama-i-bio.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011480:Protease Inhibitors; D002738:Chloroquine; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin
keywords: Allophenylnorstatine; Antimalarial drug; Aspartic protease; Drug-resistance; Plasmepsin inhibitor