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Masayuki Morita,
Hitomi Sanai,
Akiko Hiramoto,
Akira Sato,
Osamu Hiraoka,
Takaya Sakura,
Osamu Kaneko,
Araki Masuyama,
Masatomo Nojima,
Yusuke Wataya,
Hye-Sook Kim
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ABSTRACT: The endoperoxide artemisinin is a current first-line antimalarial and a critical component of the artemisinin-based combination therapies (ACT) recommended by WHO for treatment of Plasmodium falciparum, the deadliest of malaria parasites. However, recent emergence of the artemisinin-resistant P. falciparum urged us to develop new antimalarial drugs. We have shown that synthetic endoperoxides N-89 and its hydroxyl derivative N-251 had high antimalarial activities both in vivo and in vitro. However, the mechanisms including the cellular targets of the endoperoxide antimalarials are not well understood. Thus, in this study, we employed chemical proteomics to survey potential molecular targets of endoperoxides by evaluating P. falciparum proteins capable to associate with endoperoxide structure (N-346, a carboxyamino derivative of N-89). We also analyzed the protein expression profiles of malaria parasites treated with N-89 or N-251 to explore possible changes associated with the drug action. From these experiments, we found that P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC) had high affinity to the endoperoxide structure (N-346) and was decreased by treatment with N-89 or N-251. PfERC is a member of CREC protein family, a potential disease marker and also a potential target for therapeutic intervention. We propose that the PfERC is a strong candidate of the endoperoxide antimalarial's target.
Journal of Proteome Research 10/2012; · 5.11 Impact Factor
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Akira Sato,
Satoru Kawai,
Akiko Hiramoto, Masayuki Morita,
Natsuki Tanigawa,
Yukari Nakase,
Yuka Komichi,
Masahiro Matsumoto,
Osamu Hiraoka,
Kazuyuki Hiramoto,
Hidekazu Tokuhara,
Araki Masuyama,
Masatomo Nojima,
Kazutaka Higaki,
Hikoya Hayatsu,
Yusuke Wataya,
Hye-Sook Kim
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ABSTRACT: Malaria is one of the world's deadliest diseases and is becoming an increasingly serious problem as malaria parasites develop resistance to most of the antimalarial drugs used today. We previously reported the in vitro and in vivo antimalarial potencies of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) and 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Plasmodium falciparum and Plasmodium berghei parasites. To improve water-solubility for synthetic peroxides, a variety of cyclic peroxides having carboxyl functionality was prepared based on the antimalarial candidate, N-251, and their antimalarial activities were determined. The reactions of N-89 and its derivatives with Fe(II) demonstrated a highly efficient formation of the corresponding carbon radical which may be suspected as a key for the antiparasitic activity.
Parasitology International 09/2011; 60(4):488-92. · 2.13 Impact Factor
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Akira Sato,
Akiko Hiramoto, Masayuki Morita,
Masahiro Matsumoto,
Yuka Komich,
Yukari Nakase,
Natsuki Tanigawa,
Osamu Hiraoka,
Kazuyuki Hiramoto,
Hikoya Hayatsu,
Kazutaka Higaki,
Satoru Kawai,
Araki Masuyama,
Masatomo Nojima,
Yusuke Wataya,
Hye-Sook Kim
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ABSTRACT: Plasmodium falciparum, the major causative parasite for the disease, has acquired resistance to most of the antimalarial drugs used today, presenting an immediate need for new antimalarial drugs. Here, we report the in vitro and in vivo antimalarial activities of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against P. falciparum and Plasmodium berghei parasites. The N-251 showed high antimalarial potencies both in the in vitro and the in vivo tests (EC(50) 2.3×10(-8) M; ED(50) 15 mg/kg (per oral)). The potencies were similar to that of artemisinin in vitro and greater than artemisinin's activity in vivo (p.o.). In addition, N-251 has little toxicity: a single oral administration at 2000 mg/kg to a rat gave no health problems to it. Administration of N-251 to mice bearing 1% of parasitemia (per oral 68 mg/kg, 3 times a day for 3 consecutive days) resulted in a dramatic decrease in the parasitemia: all the 5 mice given N-251 were cured without any recurrence, with no diarrhea or weight loss occurring in the 60 days of experiment. N-251 deserves more extensive clinical evaluation, desirably including future trials in the human.
Parasitology International 04/2011; 60(3):270-3. · 2.13 Impact Factor
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Toshie Taniguchi,
Takashi Kumagai,
Rieko Shimogawara,
Shizuko Ichinose,
Akiko Hiramoto,
Akira Sato, Masayuki Morita,
Masatomo Nojima,
Hye-Sook Kim,
Yusuke Wataya,
Nobuo Ohta
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ABSTRACT: 1,2,6,7-Tetraoxaspiro[7.11]nonadecane (N-89) is a chemically synthesized compound with good efficacy against malaria parasites. We observed strong anti-schistosomal activities of N-89 both in vitro and in vivo. In a murine model with experimental infection of Schistosoma mansoni, orally administered N-89 at the dose of 300 mg/kg resulted in a significant reduction in worm burden (63%) when mice were treated at 2-weeks postinfection. Strong larvicidal effects of N-89 were confirmed in vitro; schistosomula of S. mansoni were killed by N-89 at an EC50 of 16 nM. In contrast, no significant reduction in worm burden was observed when N-89 was administered at 5 weeks postinfection in vivo. However, egg production was markedly suppressed by N-89 treatment at that time point. On microscopic observation, the intestine of N-89-treated female worms seemed to be empty compared with the control group, and the mean body length was significantly shorter than that of controls. Nutritional impairment in the parasite due to N-89 treatment was possible, and therefore quantification of hemozoin was compared between parasites with or without N-89 treatment. We found that the hemozoin content was significantly reduced in N-89 treated parasites compared with controls (P<0.001). The surface of adult worms was observed by scanning and transmission electron microscopy, but there were no apparent changes. Taken together, these observations suggested that N-89 has strong antischistosomal effects, probably through a unique mode of drug efficacy. As N-89 is less toxic to mammalian host animals, it is a possible drug candidate against schistosomiasis.
Parasitology International 03/2011; 60(3):231-6. · 2.13 Impact Factor
