New antiamlarial drug development research against drug-resistant Plasmodium falciparum

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 16390031
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: OKAYAMA UNIVERSITY
• Principal Investigator: KIM Hyesook Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (70314664)
• Co-Investigator(Kenkyū-buntansha): WATAYA Yusuke Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (90127598) ; KIMURA Mikio National Institute of infectious Diseases, Infectious Disease Surveillance Center, Leader, 感染症情報センター, 室長 (90114462) ; KAWAI Satoru Dokkyo Medicinal University, School of medicine, Associate Professor, 医学部, 助教授 (70275733)
• Project Period (FY): 2004 – 2005
• Keywords: malaria / endoperoxides / drug-resistant / antimalarials / johzan alkaloid / mechanism analysis

Research Abstract

Our research objective is development of new antiamalarial drug against drug-resistant Plasmodium falciparum and our study is advanced for the purpose of contributing to the malaria suppression. For the antimalarial action mechanism of our research, we using endopeoxides, which is the organic compound and these chemical compounds with the selection of the high antimalarial action, and other compound, johzan alkaloid analogs, which are natural, product derived from Dichroa febrifuga.
The research result of this study is shown at the following.
1.Mechanism of endoperoxide antimalarials was comprehensively analyzed. Base on the 2 dimensional electrophoretic conditions for separation of parasite proteins, it came out in comparison with the pattern of the protein with the difference of control- and endoperoxide treated protein pattern. Different protein spots were cut and analyzed with MALDI- TOF/MS, and the protein was identified. As a result, several parasite proteins were detected, such as cytosketal protein, nutrient related protein and client protein of parasite. Furthermore, drug target of endoperoxide in malaria parasite was detected.
2.Endoperoxide resistant P.falciparum strain (parasite grow under the 1 × 10^<-7>M of drug pressure) were acquired in vitro culture using drug pressure of endoperoxide and cloning technique.
3.One of ten analogs of Johzan alkaloids has high antiamlarial activity with low cytotoxicity.
4.Transcriptome analysis for the dissolving the mefloquine-resistant mechanism of P.falciparum was done. As a results, gene expression level of pfmdr-1 and pfmrp, were not changed. Combination treatment of anti-tuberculosis and endoperoxide shows reverse effect against mefloquine-resistant P.falciparum.
Base on the upper results, we would like to decide the target molecule of malaria parasite for endoperoxide

Research Products

• [Journal Article] Antimalarial Effect of Bis-pyridinium Salts, N, N'-Hexamethylenebis(4-carbamoyl-1- alkvlpyridinium bromide). (2006)
  • Author(s): Fujimoto, K., Morisaki, D., Yoshlda, M., Namba, T, Kim, T.-S., Wataya, Y., Kourai, H., Kakuta, H., Sasaki,K
  • Journal Title: Bioorg. Med. Chem. Lett. 16 Pages: 2758-2760
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Antimalarial Effect of Bis-pyridinium Salts, N,N'-Hexamethylenebis (4-carbamoyl-1-alkylpyridinium bromide). (2006)
  • Author(s): Fujimoto, K., Morisaki, D., Yoshida, M., Namba, T., Kim, H.-S., Wataya, Y., Kourai, H., Kakuta, H., Sasaki, K.
  • Journal Title: Bioorg.Med.Chem.Lett. 16 Pages: 2758-2760
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Co-catalyzed autoxidation of alkene in the presence of silane The effect of the structure of silanes on the efficiencyof the reaction and on the product distribution. (2005)
  • Author(s): Wu, J, -M., Kunikawa, S., Tokuyasu, T., Masuyama, A., Nojima, M., Kim, H.-S., Waraya,Y.
  • Journal Title: Tetrahedrol, 61 Pages: 9961-9968
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis and biological activity of fatty acid conjugate of quinine. (2005)
  • Author(s): Fumura, N., lzumi, M., Nakajima, S., Shimizu, S., Kim, H, -S., Wataya, Y., Baba,N.
  • Journal Title: Biosci. Biotech. Biochem. 69(11) Pages: 2250-2253
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis and in vitro antimalarial activity of some simple peroxyplakoric acid analogues. (2005)
  • Author(s): Liu, H., Jin, H.Zhang, Q., Wu, Y., Kim, H, -S, Wataya,Y.
  • Journal Title: Chinese J.Chem. 23 Pages: 1469-1473
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis and evaluation of b-carbolinium cations as new antimalarial agents based on pi-delocalized lipophilic cation (DLC) hypothesis. (2005)
  • Author(s): Takasu, K, Shimogama, T, Saiin, C, Kim.H.-S., Wataya, Y., Brun, R, Ihara,M
  • Journal Title: Chem. Pharm. Bull., 53(6) Pages: 653-661
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis of novel siRNAs having thymidine dimers consisting of a carbamate or an urea linkage at their 3 ' overhang regions and their ability to suppress human RNase L protein expression. (2005)
  • Author(s): Ueno, Y., Naito, T., Kawada, K., Shibata, A., Kim.H.-S., Wataya, Y., Kitada,Y.
  • Journal Title: Biol.Biophy.Res.Comm. 20,330(4) Pages: 1168-1175
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis of 5'-methylenearisteromycin and its 2-fluoro congener with potent antimalarial activity due to the parasite S-adenosyl homocysteine hydrolase Inhibition. (2005)
  • Author(s): Takagi, T., Sukeda, M., Kim.H.-S., Wataya, Y., Kitada, Y., Matsuda, A., Shuto, S.
  • Journal Title: Org.Bjomol. Chem., 3 Pages: 1245-1251
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 1, 2, 4, 5 - Tetraoxan cycloalkanes : Synthesis and Antimalarial Activity. (2005)
  • Author(s): Masuyama, A., Wu, J-M., Nojima, M., Kim, H-S., Wataya,Y.
  • Journal Title: Mlnl-Reviews Med. chem. 5 Pages: 1035-1043
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sequence analysis of the 5'-flanking regions of human dihydropyrimidine dehydrogenase gene : Identification of a new polymorphism related with effects of 5-fluorouracil. (2005)
  • Author(s): Hasegawa, T., Kim, H-S., Fukushima, M.,, Wataya, Y.
  • Journal Title: Nucleosides Nucleotides Nucleic Acids, 24(4) Pages: 233-242
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibitory Mechanisms of 1-(3-C-ethynyl-b-D-ribo-pentofuranosyl) uracil ( EUrd ) on RNA Synthesis. (2005)
  • Author(s): Yokogawa, T., Kanda, H., Takatori, S., Takenaka, K., Naito, T., Sasaki, T., Matsuda, A., Fukushima, M., Kim, H-S., Wataya,Y.
  • Journal Title: Nucleosides Nucleotides Nucleic Acids, 24(3) Pages: 227-232
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gastrodia elata Blume and an active component, phydroxybenzyl alcohol reduce focal ischemic brain injury through antioxidant related gene expressions (2005)
  • Author(s): Yu, Kim, Lee, Han, Lee, Kim, H-S., Hong.J, Kang, S
  • Journal Title: Biol.Pharm.Bull. 28(6) Pages: 1016-1020
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Co-catalyzed autoxidation of alkene in the presence of silane. The effect of the structure of silanes on the efficiency of the reaction and on the product distribution. (2005)
  • Author(s): Wu, J.-M., Kunikawa, S., Tokuyasu, T., Masuyama, A., Nojima, M., Kim, H.-S., Wataya, Y.
  • Journal Title: Tetrahedron 61 Pages: 9961-9968
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis and biological activity of fatty acid conjugate of quinine. (2005)
  • Author(s): Kumura, N., Izumi, M.Nakajima, S., Shimizu, S., Kim, H.-S., Wataya, Y., Baba, N.
  • Journal Title: Biosci.Biotech.Biochem. 69(11) Pages: 2250-2253
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis and in vitro antimalarial activity of some simple peroxyplakoric acid analogues. (2005)
  • Author(s): Liu, H., Jin, H., Zhang, Q., Wu, Y., Kim, H.-S., Wataya, Y.
  • Journal Title: Chinese J.Chem. 23 Pages: 1469-1473
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis and evaluation of b-carbolinium cations as new antimalarial agents based on pi-delocalized lipophilic cation (DLC) hypothesis. (2005)
  • Author(s): Takasu, K, Shimogama, T, Saiin, C, Kim, H.-S, Wataya, Y, Brun, R, Ihara, M.
  • Journal Title: Chem.Pharm.Bull. 53(6) Pages: 653-661
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis of novel siRNAs having thymidine dimers consisting of a carbamate or an urea linkage at their 3' overhang regions and their ability to suppress human RNase L protein expression. (2005)
  • Author(s): Ueno, Y., Naito, T., Kawada, K., Sibata, A., Kim, H.-S., Wataya, Y., Kitabe, Y.
  • Journal Title: Biol.Biophy.Res.Comm. 20,330(4) Pages: 1168-1175
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis of 5'-methylenearisteromycin and its 2-fluoro congener with potent antimalarial activity due to the parasite S-adenosyl homocysteine hydrolase Inhibition. (2005)
  • Author(s): Takagi, T., Sukeda, M., Kim, H.-S., Wataya, Y., Kitade, Y., Matsuda, A., Shuto, S.
  • Journal Title: Org.Biomol.Chem. 3 Pages: 1245-1251
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sequence analysis of the 5'-flanking regions of human dihydropyrimidine dehydrogenase gene : Identification of a new polymorphism related with effects of 5-fluorouracil. (2005)
  • Author(s): Hasegawa, T., Kim, H.-S., Fukushima, M., Wataya, T.
  • Journal Title: Nucleosides Nucleotides Nucleic Acids 24(4) Pages: 233-242
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibitory Mechanisms of 1-(3-C-ethynyl-b-D-ribo-pentofuranosyl)uracil (EUrd) on RNA Synthesis. (2005)
  • Author(s): Yokogawa, T., Kanda, H., Takatori, S., Takenaka, K., Naito, T., Sasaki, T., Matsuda, A., Fukushima, M., Kim, H.-S., Wataya, Y.
  • Journal Title: Nucleosides Nucleotides Nucleic Acids 24(3) Pages: 227-232
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gastrodia elata Blume and an active component, p-hydroxybenzyl alcohol reduce focal ischemic brain injury through antioxidant related gene expressions (2005)
  • Author(s): Yu, S., Kim, J., Lee, C., Han, J., Lee, J., Kim, H.-S., Hong, J., Kang, S.
  • Journal Title: Biol.Pharm.Bull. 28(6) Pages: 1016-1020
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 1,2,4,5-Tetraoxan cycloalkanes : Synthesis and Antimalarial Activity. (2005)
  • Author(s): Masuyama, A., Wu, J-M., Nojima, M., Kim, H.-S., Wataya, Y.
  • Journal Title: Mini-Reviews Med.Chem. 5 Pages: 1035-1043
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Duffy antigen is important for lethality of the lethal strain P. yoelii 17XL (2004)
  • Author(s): Akimitsu, N., Kim, H-S., Ono, K., Wataya, Y., Torii, M.Sekimizu,K.
  • Journal Title: Parasltolgy Res. 93 Pages: 499-503
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Antimalarial Activity of Lavandulyl Flavanones Isolated from the Roots of Sophora flavescens. (2004)
  • Author(s): Kim, Y.-C, Kim, H.-S., Wataya, Y., Sohn, D.-H., Kang, T, -H., Kim, M.-S., Kim, Y.-M., Lee, K.-M., Chang, J.-D., Park,H.
  • Journal Title: Biol.Pharm.Bull. 25 Pages: 748-750
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Duffy antigen is important for lethality of the lethal strain P.yoelii 17XL, (2004)
  • Author(s): Akimitsu, N., Kim, H.-S., Ono, K., Wataya, Y., Torii, M., Sekimizu, K.
  • Journal Title: Parasitolgy Res. 93 Pages: 499-530
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antimalarial Activity of Lavandulyl Flavanones Isolated from the Roots of Sophora flavescens. (2004)
  • Author(s): Kim, Y.-C., Kim, H.-S., Wataya, Y., Sohn, D.-H., Kang, T.-H., Kim, M.-S., Kim, Y.-M., Lee, K.-M., Chang, J.-D., Rark, H.
  • Journal Title: Biol.Pharm.Bull. 27(5) Pages: 748-750
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] p Delocalized b-carbolinium cations as potential antiamlarials. (2004)
  • Author(s): Takasu, K., Shimogama, T., Saiin, C., Kim, H.-S., Wataya, Y., Ihara, M.
  • Journal Title: Bioorg.Med.Chem.Lett. 14 Pages: 1689-1692
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 実験医学 (2005)
  • Author(s): 綿矢 有佑, 金 惠淑
  • Total Pages: 5
  • Publisher: 抗マラリヤ薬の開発 : 過去-現在-未来
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 抗原虫薬 (2004)
  • Author(s): 金 惠淑, 綿矢 有佑, 木村幹男, 益山新樹, 野島正朋
  • Total Pages: 5
  • Publisher: 臨床と微生物
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] ヘムへの配置能を有する抗マラリア活性化合物 (2006)
  • Inventor(s): 樋口恒彦, 大宮弘久, 梅澤直樹, 金惠子淑, 綿矢 有佑
  • Industrial Property Rights Holder: 樋口恒彦
  • Industrial Property Number: 特願2006-49678
  • Filing Date: 2006-02-28
  • Description: 「研究成果報告書概要(和文)」より