Faculty Profiles - KIM Hye-Sook

Papers - KIM Hye-Sook

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Toloese Generates Nitric Oxide through Natural Radiation of Far Infrared Rays, Reducing Serum Glucose, Cholesterol, and Triglycerides. Reviewed International journal

Min-Ho Yeo, Young-Hyeon Lee, Mi-Jin Ryu, Yong-Hak Choi, Hye-Sook Kim, Kyung-Soo Chang

Healthcare (Basel, Switzerland) 12 ( 12 ) 2024.6

Language：English Publishing type：Research paper (scientific journal)

Toloese, a bed composition, is formulated with a combination of minerals of various wavelengths by utilizing a specific ratio and particle size. A maturation mixing technique is used without additional compression processes, resulting in the natural formation of numerous fine pores in the bed structure. At 40 °C, far infrared radiation in the range of 5-20 μm is emitted with a 0.916 radiant ratio, and the measured emitted radiant energy is 3.69 × 102 W/m2·μm. This study aimed to investigate the influence of far infrared radiation emitted from a Toloese bed on endogenous nitric oxide production. Clinical trials were conducted with 20 healthy adults aged 20 years. Blood samples were collected before and after Toloese bed usage for 1 h daily for 3 weeks. Nitric oxide levels in the saliva and blood of men and women significant increased after they used the Toloese bed for 1 h. Additionally, sweating sharply increased in the upper and lower body regions after Toloese bed usage. No hematological changes or adverse effects were observed, but blood glucose, cholesterol, and triglycerides decreased after Toloese bed usage compared with those before Toloese bed usage. These findings demonstrated that far infrared radiation emitted by the Toloese bed induced endogenous nitric oxide production and contributed to significant reductions in blood glucose, cholesterol, and triglyceride levels.

DOI： 10.3390/healthcare12121227

新規抗マラリア薬候補化合物,1,2,6,7-tetraoxaspiro[7.11]nonadecane(N-89)の作用機序に関する研究

坂本沙祐里, 森田将之, 平本一幸, 金恵淑, 綿矢有佑, 平岡修

就実大学薬学雑誌 11 9 - 19 2024.1

Language：Japanese Publisher：就実大学薬学部「就実大学薬学雑誌」編集委員会

1,2,6,7-tetraoxaspiro[7.11]-nonadecane(N-89)のマラリア小胞体局在性カルシウム結合タンパク質(PfERC)に対する種々のin vitro実験から、鉄イオンと細胞内モータータンパク質が関与しN-89の作用機序の解明につながるような知見が得られたので報告した。N-89を生理的環境に近い条件にて電子スピン共鳴法(ESR)測定を行った。その結果、Fe2+の存在下でラジカルを産生することが示された。次に、N-89処理がPfERCに及ぼす影響についてSDS-PAGEにより解析を行い、環状過酸化化合物がFe2+の存在下において特異的にPfERCを切断するものと考えられた。さらに、Fe3+の存在によりPfERCのAggregates形成が誘導されるが、この誘導はEDTAやDFOの添加により解消されることが分かった。PfERCはPlm Xが関与するEgress/Invasion経路のタンパク質分解カスケードおよび細胞質内モータータンパク質、PfGAP45をCa2+存在下で調節することによって、Merozoite体とヘモゾインのEgress/Invasionを進行させていると考えられた。

Oral activity of the antimalarial endoperoxide 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Leishmania donovani complex Reviewed

Kofi Dadzie Kwofie, Kai Sato, Chizu Sanjoba, Akina Hino, Rieko Shimogawara, Michael Amoa-Bosompem, Irene Ayi, Daniel A. Boakye, Abraham K. Anang, Kyung-Soo Chang, Mitsuko Ohashi, Hye-Sook Kim, Nobuo Ohta, Yoshitsugu Matsumoto, Shiroh Iwanaga

PLOS Neglected Tropical Diseases 13 ( 3 ) e0007235 - e0007235 2019.3

Potent Antimalarial Activity of Two Arenes Linked with Triamine Designed To Have Multiple Interactions with Heme. Reviewed International journal

Yosuke Sakata, Kosuke Yabunaka, Yuko Kobayashi, Hirohisa Omiya, Naoki Umezawa, Hye-Sook Kim, Yusuke Wataya, Yoshimi Tomita, Yosuke Hisamatsu, Nobuki Kato, Hirokazu Yagi, Tadashi Satoh, Koichi Kato, Haruto Ishikawa, Tsunehiko Higuchi

ACS medicinal chemistry letters 9 ( 10 ) 980 - 985 2018.10

Language：English

Based on the idea that compounds designed to exhibit high affinity for heme would block hemozoin formation, a critical heme-detoxification process for malarial parasites, we synthesized a series of compounds with two π-conjugated moieties at terminal amino groups of triamine. These compounds exhibited moderate to high antimalarial activities in vitro toward both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. In a P. berghei-infected mouse model, 3a and 12a showed potent antimalarial activities compared to artesunate, as well as a prolonged duration of antimalarial effect. We found a good correlation between protective activity against hemin degradation and antimalarial activity. Compounds 8b and 3a strongly inhibited hemozoin formation catalyzed by heme detoxification protein.

DOI： 10.1021/acsmedchemlett.8b00222

Multiple antiviral activities of the antimalarial and anti-hepatitis C drug candidates N-89 and N-251. Reviewed International journal

Youki Ueda, Weilin Gu, Hiromichi Dansako, Hye-Sook Kim, Sayaka Yoshizaki, Nobuaki Okumura, Tomohiro Ishikawa, Hironori Nishitsuji, Fumihiro Kato, Takayuki Hishiki, Shinya Satoh, Koji Ishii, Michiaki Masuda, Kunitada Shimotohno, Masanori Ikeda, Nobuyuki Kato

Biochemistry and biophysics reports 15 1 - 6 2018.9

Language：English

The chemically synthesized endoperoxide compound N-89 and its derivative N-251 were shown to have potent antimalarial activity. We previously demonstrated that N-89 and N-251 potently inhibited the RNA replication of hepatitis C virus (HCV), which belongs to the Flaviviridae family. Since antimalarial and anti-HCV mechanisms have not been clarified, we were interested whether N-89 and N-251 possessed the activity against viruses other than HCV. In this study, we examined the effects of N-89 and N-251 on other flaviviruses (dengue virus and Japanese encephalitis virus) and hepatitis viruses (hepatitis B virus and hepatitis E virus). Our findings revealed that N-89 and N-251 moderately inhibited the RNA replication of Japanese encephalitis virus and hepatitis E virus, although we could not detect those anti-dengue virus activities. We also observed that N-89 and N-251 moderately inhibited the replication of hepatitis B virus at the step after viral translation. These results suggest the possibility that N-89 and N-251 act on some common host factor(s) that are necessary for viral replications, rather than the possibility that N-89 and N-251 directly act on the viral proteins except for HCV. We describe a new type of antiviral reagents, N-89 and N-251, which are applicable to multiple different viruses.

DOI： 10.1016/j.bbrep.2018.05.007

Insights into the mode of action of 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N-89) against adult Schistosoma mansoni worms Reviewed

Blay E. A, Kumagai T, Yamabe M, Hino A, Shimogawara R, Kim H.-S, Sato A, Ichimura K, Ayi I, Iwanaga S, Ohta N

Parasitology International 67 ( 4 ) 403 - 412 2018.8

Language：English Publishing type：Research paper (scientific journal)

Control of morbidity associated with schistosomiasis via chemotherapy largely relies on the drug praziquantel. Repeated therapy with praziquantel has created concerns about the possible selection of resistant worms and necessitated the search for novel drugs to treat schistosomiasis. Here, a murine model was infected with Schistosoma mansoni and treated with oral 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N-89), which caused a significant reduction in fecundity and egg burden and reduced morbidity when administered at 5-weeks post-infection. The analysis showed that the mode of action occurred through the ingestion of activated N-89 by the worms, and that there was no direct external effect on the S. mansoni worms. Ultrastructural analysis of the treated worms showed disruptions in the gut lumen and the presence of large volumes of material, suggestive of undigested blood meals or red blood cells. In addition, there were reduced vitelline cells in female worms and damage to sub-tegmental musculature in male worms. Eggs recovered from the treated mice showed both damage to the eggs and the production of immature eggs. Expression of mRNA responsible for gut and digestive function and egg production was also significantly affected by N-89 treatment, whereas control genes for musculature showed no significant changes. Thus, N-89 drastically affected the total digestive function and egg production of S. mansoni worms. Physiological processes requiring heme uptake such as egg production and eggshell formation were subsequently affected, suggesting that the compound could be a possible therapeutic drug candidate for schistosomiasis control.

DOI： 10.1016/j.parint.2018.03.006

Potential of synthetic endoperoxides against Trichomonas vaginalis in vitro Reviewed

Min-Young Seo, Jae-Sook Ryu, Akira Sato, Yuji Kurosaki, Kyung-Soo Chang, Hye-Sook Kim

PARASITOLOGY INTERNATIONAL 66 ( 5 ) 619 - 621 2017.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Metronidazole is well known for medicine against Trichomonas vaginalis infection, but it has side effects though it is effective, and especially because reports of metronidazole-tolerant species are increasing, the development of new medicine is being required. Here, we noticed the killing effects of endoperoxide compounds, N-89 and N-251 as new antimalarial drug candidates, on T. vaginalis and searched the possibility of development of new medicine. We added each of metronidazole, artemisinin, and two of new endoperoxides (N-89 and N-251) to metronidazole-resistant and -sensitive species and compared its anti-trichomonal efficacy. For metronidazole, IC50 value, 50% of killing concentration for T. vaginalis, was very low for metronidazole-sensitive isolates (11.7 to 22.8 mu M), but was high for metronidazole-resistant ones (182.9 to 730.4 mu M). The IC50 values of N-89 and N-251 were 41.0 to 60.0 mu M, and 82.0 to 300.0 mu M for metronidazole-sensitive and-resistant isolates, respectively. In conclusion, we found the endoperoxides, N-89 and N-251, have anti-trichomonal effect against metronidazole-resistant T. vaginalis as well as metronidazole-sensitive ones. These results indicate that the anti-richomonal effects for our endoperoxides are equivalent or better in metronidazole-resistant T. vaginalis in comparison to metronidazole.

DOI： 10.1016/j.parint.2017.05.008

Role of the uridine/cytidine kinase 2 mutation in cellular sensitiveness toward 3-ethynylcytidine treatment of human cancer cells Reviewed

Akira Sato, Takeshi Takano, Akiko Hiramoto, Tomoharu Naito, Akira Matsuda, Masakazu Fukushima, Yusuke Wataya, Hye-Sook Kim

ANTI-CANCER DRUGS 28 ( 7 ) 781 - 786 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

A nucleosidic medicine, 1-(3-C-ethynyl--d-ribo-pentofuranosyl)cytosine [3-ethynylcytidine (ECyd)], is a potent inhibitor of RNA polymerase I and shows anticancer activity to various human solid tumors in vitro and in vivo. ECyd is phosphorylated to 3-ethyntlcytidine 5-monophosphate by uridine/cytidine kinase 2 (UCK2) and subsequently further to diphosphate and triphosphate (3-ethyntlcytidine 5-diphosphate, 3-ethyntlcytidine 5-triphosphate). 3-Ethyntlcytidine 5-triphosphate is an active metabolite that can inhibit RNA polymerase I competitively, causing cancer cell death. Here, to identify the UCK2 mutation for detecting responder or nonresponder to ECyd, we investigated the relationship between point mutation of the UCK2 gene and response to ECyd in various human solid tumors. We identified several functional point mutations including the splice-site mutation of the UCK2 gene IVS5+5 G>A. In addition, we found that the IVS5+5 G>A variant generates an aberrant mRNA transcript, namely, truncated mRNA was produced and normal mRNA levels were markedly decreased in the ECyd-resistant cancer cell line HT1080. We concluded that these findings strongly suggest that the IVS5+5 G>A variant would affect the expression level of the UCK2 transcript, resulting in decreased sensitivity to ECyd.

DOI： 10.1097/CAD.0000000000000519

Evaluation of preclinical antimalarial drugs, which can overcome direct acting antivirals-resistant hepatitis C viruses, using the viral reporter assay systems Reviewed

Youki Ueda, Hiromichi Dansako, Shinya Satoh, Hye-Sook Kim, Yusuke Wataya, Hiroyuki Doi, Masanori Ikeda, Nobuyuki Kato

VIRUS RESEARCH 235 37 - 48 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a major global health problem. Recently developed treatments with direct-acting antivirals (DAAs) have largely improved the sustained virologic response rate of patients with chronic hepatitis C. However, this approach is still hindered by its great expense and the problem of drug resistance. Using our cell-based HCV assay systems, we reported that the preclinical antimalarial drugs N-89 and N-251 exhibited potent anti-HCV activities. In this study we used our assay systems to evaluate the anti-HCV activities of six kinds of DAAs individually or in combination with N-89 or N-251. The results showed that the DAAs had potent anti-HCV activities and N-89 or N-251 contributed additive or synergistic effect. Using DAA-resistant HCV-RNA-replicating cells, which were prepared by continuous treatment with each DAA, we demonstrated that N-89 and N-251 could overcome all of the DAA-resistant HCVs. These preclinical drugs would have been potential as components of a therapeutic regimen that also included combinations of various DAAs. In addition, sequence analysis of the NS3-NS5B regions of the DAA-resistant HCV genomes newly found several amino acid (aa) substitutions that were suggested to contribute to DAA-resistance in addition to the aa substitutions already known to cause DAA-resistance. Among these new aa substitutions, we found that two substitutions in the NS3 region (D79G and S174Y) contributed to simeprevirand/or asunaprevir-resistance.

DOI： 10.1016/j.virusres.2017.03.015

Novel synthetic compounds with endoperoxide structure damage juvenile stage of Schistosoma mansoni by targeting lysosome-like organelles Reviewed

Masafumi Yamabe, Takashi Kumagai, Rieko Shimogawara, Emmanuel Awusah Blay, Akina Hino, Koichiro Ichimura, Akira Sato, Hye-Sook Kim, Nobuo Ohta

PARASITOLOGY INTERNATIONAL 66 ( 1 ) 917 - 924 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

The new synthetic compound 1,2,6,7-tetraoxaspiro[7.11]nonadecan (N-89), a novel anti-malaria drug candidate, is also a promising drug candidate against schistosomiasis with killing effects against juvenile stage of S. mansoni. In order to investigate how N-89 kills schistosomes, we used a derivative of N-89, 6-(1,2,6,7-tetraoxaspiro[7.11] nonadec-4-yl)hexan-1-ol (N-251), which enables us to conjugate with fluorescent reagents. Firstly, N-251 showed strong killing effects to larvae of S. mansoni in vitro. Ultrastructural analysis showed the disruptions of the lysosome-like organelles or the acetabular glands, followed by cytoplasmic lysis inside the worm body in N-251 -treated group under electron microscopy. For rhodamine-conjugated N-251 and organelle markers, we observed that N-251 accumulated in acidic organelle. In addition, LysoTracker signals in these acidic organelles disappeared in N-251-treated group over time. Finally, we observed that the activity of cathepsin B, a lysosome-specific enzyme, was also decreased together with alternation of acidic organelle marker signal by N-251-treated group. These results suggested that our synthesized compounds induced the dysfunction or the disruption of acidic lysosome-like organelles and finally led to worm death. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.parint.2016.10.013

In vitro inhibition of Toxoplasma gondii by the anti-malarial candidate, 6-(1,2,6,7-tetraoxaspiro[7.1 1]nonadec-4-yl)hexan-1-ol Reviewed

Chun-Feng Xin, Hye-Sook Kim, Akira Sato, Hak-Jae Lee, You-Won Lee, Kyoung-Ho Pyo, Eun-Hee Shin

PARASITOLOGY INTERNATIONAL 65 ( 5 ) 494 - 499 2016.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

An anti-malarial candidate, 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-l-ol (N-251), was studied to characterize its potential as a novel anti-Toxoplasma gondii drug. In the present study, IC50 and LC50 of N-251 on host cells and T. gondii were compared to those of artemisinin and sulfadiazine. The IC50 on Huh-7 cells was 10.19 mu g/ml, 67.69 mu g/ml and 310.17 mu g/ml for N-251, artemisinin, and sulfadiazine, respectively. The LC50 for anti-T. gondii effect was shown to be 1.11 mu g/ml, 5.79 mu g/ml, and 5.45 mu g/ml for N-251, artemisinin and sulfadiazine, respectively. N-251 concentration causing complete parasiticidal effect with minimal cytotoxicity on host cells was determined to be 5 mu g/ml. Additionally, the anti-T. gondii effect of N-251 was confirmed by ultrastructural changes, loss of organelles, degenerated morphology and the increase of amylopectin as detected by transmission electron microscope (TEM). Accordingly, the present study suggests that the anti-malarial synthetic endoperoxide, N-251, is an emerging drug candidate more effective than artemisinin and sulfadiazine. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.parint.2016.06.013

MicroRNA-351 Regulates Two-Types of Cell Death, Necrosis and Apoptosis, Induced by 5-fluoro-2'-deoxyuridine Reviewed

Akira Sato, Takuya Omi, Akihiro Yamamoto, Akito Satake, Akiko Hiramoto, Mitsuko Masutani, Sei-ichi Tanuma, Yusuke Wataya, Hye-Sook Kim

PLOS ONE 11 ( 4 ) 2016.4

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Cell-death can be necrosis and apoptosis. We are investigating the mechanisms regulating the cell death that occurs on treatment of mouse cancer cell-line FM3A with antitumor 5-fluoro-2'-deoxyuridine (FUdR): necrosis occurs for the original clone F28-7, and apoptosis for its variant F28-7-A. Here we report that a microRNA (miR-351) regulates the cell death pattern. The miR-351 is expressed strongly in F28-7-A but only weakly in F28-7. Induction of a higher expression of miR-351 in F28-7 by transfecting an miRNA mimic into F28-7 resulted in a change of the death mode; necrosis to apoptosis. Furthermore, transfection of an miR-351 inhibitor into F28-7-A resulted in the morphology change, apoptosis to necrosis, in this death-by-FUdR. Possible mechanism involving lamin B1 in this miR-351's regulatory action is discussed.

DOI： 10.1371/journal.pone.0153130

New antimalarial endoperoxides for drug-resistant Plasmodium falciparum: The current situation Reviewed

Kim H.-S, Katamoto A, Sato A, Wataya Y, Doi H

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 127 231 - 235 2015.12

Improvement of Oral Bioavailability of N-251, a Novel Antimalarial Drug, by Increasing Lymphatic Transport with Long-Chain Fatty Acid-Based Self-Nanoemulsifying Drug Delivery System Reviewed

Chikako Imada, Takuma Takahashi, Makoto Kuramoto, Kazufumi Masuda, Ken-ichi Ogawara, Akira Sato, Yusuke Wataya, Hye-Sook Kim, Kazutaka Higaki

PHARMACEUTICAL RESEARCH 32 ( 8 ) 2595 - 2608 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER/PLENUM PUBLISHERS

Purpose The objective of this study was to improve the absorption behavior of N-251, a novel antimalarial drug, by preparing an appropriate self-nanoemulsifying drug delivery system (SNEDDS).
Methods Two different types of SNEDDS formulations, medium-chain fatty acid-based SNEDDS (MC-SNEDDS) and long-chain fatty acid-based SNEDDS (LC-SNEDDS), were prepared based on pseudo-ternary phase diagram, and examined for their in vivo oral absorption behavior in rats.
Results Oral dosing of MC-SNEDDS formulations significantly improved the bioavailability (BA) of N-251 compared with N-251 powders. However, its high hepatic extraction limited the BA of N-251 to only 0.49 for MC-SNEDDS B, the best formulation of MC-SNEDDS. LC-SNEDDS formulations, especially LC-SNEDDS F provided the highest BA, 0.65, and successfully attenuated the inter-individual difference in the absorption behavior. Furthermore, it was confirmed that lymphatic transport of N-251 for LC-SNEDDS F was significantly increased up to around 3.19 times larger than that for MC-SNEDDS B. Simulation study suggested that 20 to 39% of N-251 uptaken by the small intestine would be delivered to lymphatic system after oral administration of LC-SNEDDS F.
Conclusions SNEDDS formulations significantly improved the absorption behavior of N-251 and long-chain fatty acid-based lipid further improved it by avoiding the hepatic first-pass elimination.

DOI： 10.1007/s11095-015-1646-x

Stage specific activity of synthetic antimalarial endoperoxides, N-89 and N-251, against Plasmodium falciparum Reviewed

Masayuki Morita, Takahiko Koyama, Hitomi Sanai, Akira Sato, Akiko Hiramoto, Araki Masuyama, Masatomo Nojima, Yusuke Wataya, Hye-Sook Kim

PARASITOLOGY INTERNATIONAL 64 ( 1 ) 113 - 117 2015.2

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

We have reported that two endoperoxides, N-89 and N-251, synthesized in 2001, possess potent antimalarial activities. Aiming at their eventual use for curing malaria in humans, we have been investigating various aspects of their antimalarial actions. Here we show that N-89 and N-251 inhibit the growth of Plasmodium falciparum within human erythrocytes in vitro at its lifecycle stage 'trophozoite' specifically. It is known that artemisinin compounds, which are currently used for curing malaria, have other stage-specificities. Therefore, it is likely that the antimalarial mechanism of N-89 and N-251 differs from those of artemisinin compounds. As malaria parasites resistant to artemisinin-based combination therapy are currently emerging in some tropical regions, N-89 and N-251 are candidates for overcoming these new problems. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.parint.2014.10.007

Role of activating transcription factor 3 protein ATF3 in necrosis and apoptosis induced by 5-fluoro-20-deoxyuridine Reviewed

Akira Sato, Kentaro Nakama, Hiroki Watanabe, Akito Satake, Akihiro Yamamoto, Takuya Omi, Akiko Hiramoto, Mitsuko Masutani, Yusuke Wataya, Hye-Sook Kim

FEBS JOURNAL 281 ( 7 ) 1892 - 1900 2014.4

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Necrosis and apoptosis are the two major forms of cell death. We have studied the mechanisms that regulate the cell death observed during treatment of mouse cancer cell line FM3A with the anticancer drug 5-fluoro-2-deoxyuridine (FUdR). To detect causal differences between necrosis and apoptosis, we exploited the necrosis in original clone F28-7 and the apoptosis in its variant F28-7-A that occur on treatment with FUdR. Activating transcription factor3 (ATF3) was strongly induced during necrosis but not apoptosis. In addition, we found that ATF3 expression is regulated by heat shock protein90 (HSP90) at the mRNA stage. Knockdown of Atf3 by siRNA in the F28-7 cells resulted in apoptotic morphology rather than necrotic morphology. These results suggest that ATF3 is a cell-death regulator in necrosis and apoptosis.

DOI： 10.1111/febs.12752

Molecular dynamics and energetic perceptions of substrate recognition by thymidylate kinase Reviewed

Mahmoud Kandeel, Yoshihiro Noguchi, Kentaro Oh-Hashi, Hye-Sook Kim, Yukio Kitade

JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY 115 ( 3 ) 2089 - 2097 2014.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Plasmodium deoxyguanylate pathways are an attractive area of investigation for future metabolic and drug discovery studies due to their unusual substrate specificities. We investigated the energetic contribution to thymidylate kinase substrate binding, and the forces underlying ligand recognition. The binding constant varied from 8 x 10(4) M-1 at 290 K to 6 x 10(4) M-1 at 310 K for dGMP, and from 16 x 10(4) M-1 at 290 K to 4 x 10(4) M-1 at 310 K for TMP. Delta C (p) was estimated as -1.75 kJ mol(-1) K-1 for TMP and +2 kJ mol(-1) K-1 for dGMP. In comparison with TMP, the binding of dGMP to PfTMK produced less favorable enthalpy change, positive or favorable entropic contribution at lower temperature, positive heat capacity change, negative , positive Delta S (other), higher total solvent-exposed surface area and more or less rigid body binding. These changes indicate unfavorable conditions for proper binding and lower conformational changes, and suboptimal structural reordering during dGMP binding.

DOI： 10.1007/s10973-013-3319-5

New Preclinical Antimalarial Drugs Potently Inhibit Hepatitis C Virus Genotype 1b RNA Replication Reviewed

Youki Ueda, Midori Takeda, Kyoko Mori, Hiromichi Dansako, Takaji Wakita, Hye-Sook Kim, Akira Sato, Yusuke Wataya, Masanori Ikeda, Nobuyuki Kato

PLOS ONE 8 ( 8 ) e72519 2013.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background: Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a global health problem. Although new triple therapy (pegylated-interferon, ribavirin, and telaprevir/boceprevir) has recently been started and is expected to achieve a sustained virologic response of more than 70% in HCV genotype 1 patients, there are several problems to be resolved, including skin rash/ageusia and advanced anemia. Thus a new type of anti-HCV drug is still needed.
Methodology/Principal Findings: Recently developed HCV drug assay systems using HCV-RNA-replicating cells (e.g., HuH-7-derived OR6 and Li23-derived ORL8) were used to evaluate the anti-HCV activity of drug candidates. During the course of the evaluation of anti-HCV candidates, we unexpectedly found that two preclinical antimalarial drugs (N-89 and its derivative N-251) showed potent anti-HCV activities at tens of nanomolar concentrations irrespective of the cell lines and HCV strains of genotype 1b. We confirmed that replication of authentic HCV-RNA was inhibited by these drugs. Interestingly, however, this anti-HCV activity did not work for JFH-1 strain of genotype 2a. We demonstrated that HCV-RNA-replicating cells were cured by treatment with only N-89. A comparative time course assay using N-89 and interferon-alpha demonstrated that N-89-treated ORL8 cells had more rapid anti-HCV kinetics than did interferon-alpha-treated cells. This anti-HCV activity was largely canceled by vitamin E. In combination with interferon-alpha and/or ribavirin, N-89 or N-251 exhibited a synergistic inhibitory effect.
Conclusions/Significance: We found that the preclinical antimalarial drugs N-89 and N-251 exhibited very fast and potent anti-HCV activities using cell-based HCV-RNA-replication assay systems. N-89 and N-251 may be useful as a new type of anti-HCV reagents when used singly or in combination with interferon and/or ribavirin.

DOI： 10.1371/journal.pone.0072519

Applications of triphenylpyrylium salt-sensitized electron-transfer photo-oxygenation reactions to the synthesis of benzo-fused 1,4-diaryl-2,3- dioxabicyclo[2.2.2]octanes as new antimalarial cyclic peroxides Reviewed

Masaki Kamata, Jun-Ichi Hagiwara, Tomoko Hokari, Chiharu Suzuki, Ryohta Fujino, Sayaka Kobayashi, Hye-Sook Kim, Yusuke Wataya

Research on Chemical Intermediates 39 ( 1 ) 127 - 137 2013.1

Language：English Publishing type：Research paper (scientific journal)

Benzo-fused 1,4-diaryl-2,3-dioxabicyclo[2.2.2]octanes 4a-d (4a: Ar = C 6H5, 4b: Ar = p-FC6H4, 4c: Ar = p-MeC6H4, 4d: Ar = p-MeOC6H4) were synthesized by 2,4,6-triphenylpyrylium tetrafluoroborate (TPPBF 4)-sensitized photoinduced electron-transfer (PET)-promoted oxygenation reactions, and their in-vitro antimalarial activity was evaluated. The results showed that these substances have sufficiently high activity to enable them to serve as antimalarial lead compounds. In addition, TPPBF 4-biphenyl-cosensitized PET oxygenation was shown to be an efficient method for introduction of an O-O moiety in the construction of antimalarial cyclic peroxides. Graphical Abstract: New antimalarial bicyclic peroxides 4 were synthesized by TPPBF4-sensitized photoinduced electron-transfer oxygenation reactions.[Figure not available: see fulltext.] © 2012 Springer Science+Business Media B.V.

DOI： 10.1007/s11164-012-0637-3

Plasmodium falciparum Endoplasmic Reticulum-Resident Calcium Binding Protein Is a Possible Target of Synthetic Antimalarial Endoperoxides, N-89 and N-251 Reviewed

Masayuki Morita, Hitomi Sanai, Akiko Hiramoto, Akira Sato, Osamu Hiraoka, Takaya Sakura, Osamu Kaneko, Araki Masuyama, Masatomo Nojima, Yusuke Wataya, Hye-Sook Kim

JOURNAL OF PROTEOME RESEARCH 11 ( 12 ) 5704 - 5711 2012.12

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

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.

DOI： 10.1021/pr3005315

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