WO2010062260A1 - Inhibition de l’interaction d’un virus et d’une cellule cible - Google Patents

Inhibition de l’interaction d’un virus et d’une cellule cible Download PDF

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Publication number
WO2010062260A1
WO2010062260A1 PCT/SG2008/000456 SG2008000456W WO2010062260A1 WO 2010062260 A1 WO2010062260 A1 WO 2010062260A1 SG 2008000456 W SG2008000456 W SG 2008000456W WO 2010062260 A1 WO2010062260 A1 WO 2010062260A1
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WO
WIPO (PCT)
Prior art keywords
turmerone
virus
composition
composition according
curcuma longa
Prior art date
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PCT/SG2008/000456
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English (en)
Inventor
Ngampong Kongkathip
Sirirak Chantakru
Chanin Teerawanich
Boonsong Kongkathip
Taveesak Songserm
Original Assignee
The Thailand Research Fund
Kasetsart University
Axis Ip Holding Pte Ltd
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Publication date
Application filed by The Thailand Research Fund, Kasetsart University, Axis Ip Holding Pte Ltd filed Critical The Thailand Research Fund
Priority to KR1020117014890A priority Critical patent/KR101515822B1/ko
Priority to PCT/SG2008/000456 priority patent/WO2010062260A1/fr
Publication of WO2010062260A1 publication Critical patent/WO2010062260A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/90—Smilacaceae (Catbrier family), e.g. greenbrier or sarsaparilla
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the invention generally relates to a composition for inhibiting interactions between viruses and their target cell. More specifically, the present invention relates to a composition comprising turmerones for the inhibition of interaction between H5N1 AI virus and their target cell.
  • Curcuma longa is a plant that is widely used in Thai traditional medicine for treatment of various skin diseases and has shown several activities such as antioxidant, anti-protozoal, anti-microbial, antivenom, anti-HIV, anti-tumour and anti-inflammatory activities.
  • ar-turmerone ar-turmerone, ⁇ -turmerone and ⁇ -turmerone, which are sesquiterpenes, can be isolated from Curcuma longa.
  • ar-turmerone can also be synthesized from prochiral diols, styrene derivative and phenylacetic acid.
  • Ar-turmerone provides the spice flavour of Curcuma longa. It also possesses antiplatelet, insect repellent and antifeedant properties. Ar-turmerone also suppresses the growth of leukemia cell lines.
  • Avian Influenza virus strain H5N1 is an infectious agent that can cause illness in humans and other animal species. As H5N1 AI virus is easily transmissible between birds, it has become a major threat to the poultry industry and the farmers. The spread of H5N1 AI to almost every continent has elicited urgent need to look for methods for disease prevention and protection.
  • H5N1 AI virus targets the epithelial cell lining of the respiratory tract.
  • the binding of H5N1 AI virus to the cell surface of the target cells is mediated by hemagglutinin, which is a molecule that is expressed on the viral surface.
  • hemagglutinin binds to sialic acid molecule on the epithelial cell lining, the epithelial cell will import the virus into the cell by endocytosis.
  • the virus subsequently replicates itself within the host cell.
  • the virus then cleaves the cell surface with an enzyme known as neuraminidase and escapes from the host cell. This cleavage causes severe damage to the host cell and may result in death of the host cell.
  • Oseltamivir (commonly known as Tamiflu) is the most commonly used drug for the treatment of influenza. Oseltamivir acts as a neuraminidase inhibitor and controls H5N1 AI virus replication.
  • Tamiflu acts as a neuraminidase inhibitor and controls H5N1 AI virus replication.
  • the effectiveness of Tamiflu against H5N1 AI virus has yet to be determined.
  • the exorbitant price of the drug and the sudden demand for the drug Tamiflu is not readily available to everyone. Patients treated with Tamiflu have also reported side effects such as nausea, vomiting, dizziness and headache.
  • Tamiflu A further problem of Tamiflu is that patients treated with the drug may develop strains of flu that are resistant to the drug, thereby reducing the effectiveness of the drug in subsequent administration.
  • Other antiviral drugs such as amantadine, rimantadine and zanamavir also possess some of the above problems. It is therefore evident that new, improved and widely available drugs are required.
  • H5N1 vaccines for several of the avian H5N1 varieties in the market. However, due to the continual mutation of H5N1 AI viruses, these vaccines are of limited use.
  • a possible alternative for protecting host cells from H5N1 AI infection is by blocking or down-regulating sialic acid molecule on the epithelial cell lining.
  • sialic acid can be down-regulated by curcumin.
  • Curcumin is one component of Curcuma longa.
  • chickens which were fed with Curcuma longa mixed in their poultry feed were found to be protected from the Avian Influenza while other chickens in neighbouring farms which were not fed with Curcuma longa were infected.
  • Curcuma longa and its extracts appear to be very interesting and suitable candidates for the development of drugs against H5N1 AI virus infection.
  • compositions for inhibiting interaction between virus and target cell comprising turmerone.
  • compositions for counteracting H5N1 AI virus infection comprising turmerone and at least one pharmaceutically acceptable carrier.
  • compositions for protection against H5N1 AI virus infection comprising turmerone and at least one pharmaceutically acceptable carrier.
  • composition for inhibiting interaction between virus and target cell comprising extract of Curcuma longa containing turmerone.
  • composition for protecting chicken from viruses comprising turmerone and chicken feed.
  • FIG. 1 a shows the structural formula of ar-tunnerone for use in an embodiment of the invention
  • FIG. Ib shows the structural formula of ⁇ -turmerone for replacing the ar-turmerone of FIG. 1 a for use in the embodiment of the invention
  • FIG. Ic shows the structural formula of ⁇ -turmerone for replacing the ar-turmerone of FIG. Ia for use in the embodiment of the invention.
  • FIG. 2 shows the structural formula of curcumin in accordance with the embodiment of the invention.
  • compositions for inhibiting virus for inhibiting virus
  • processes of manufacture of such compositions as well as the uses of the composition.
  • This however, does not preclude various embodiments of the invention from other applications where fundamental principles prevalent among the various embodiments of the invention such as operational, functional or performance characteristics are required.
  • compositions for inhibiting interaction between virus and target cell include composition for inhibiting interaction between virus and target cell.
  • Each of the composition provided by the present invention comprises at least turmerone.
  • turmerone includes ar- turmerone (as shown in FIG. Ia), ⁇ -turmerone (as shown in FIG. Ib), ⁇ -turmerone (as shown in FIG. Ic) or extracts of Curcuma longa containing turmerone.
  • the compositions provided by the present invention comprise turmerones and a pharmaceutically active carrier.
  • Turmerones can be isolated from some medicinal plants such as Curcuma longa, synthesized from starting materials or purchased from the market. Turmerone can also be extracted from Curcuma longa using water, hexane, ethyl acetate, ethanol, methanol, chloroform, dichloromethane, basic water or acidic water as a solvent. Examples demonstrating extraction of turmerone from Curcuma longa using hexane, ethyl acetate and ethanol will be described hereinafter.
  • Turmeric Curcuma longa L., Zingiberaceae
  • hexane turmeric extract To obtain hexane turmeric extract, the dry rhizomes of Curcuma longa (1.15kg) were extracted with hexane for 8h by soxhlet extractor. The hexane solution was concentrated to dryness in a rotary evaporator to yield hexane turmeric extract (36.88g, 3.21% dry wt.) as a yellow oil.
  • Ethyl acetate turmeric extract To obtain ethyl acetate turmeric extract, the dry rhizomes of Curcuma longa (1Og) were extracted with ethyl acetate for 8h by soxhlet extractor. The solution was concentrated to dryness under vacuum to yield ethyl acetate turmeric extract (2.69 g, 26.9% dry wt.) as a dark red gum.
  • ethanol turmeric extract the dry rhizomes of Curcuma longa (1.15kg) were extracted with ethanol for 8h by soxhlet extractor. The solution was evaporated to dryness under vacuum to afford the ethanol turmeric extract (23Og, 20% dry wt.) as a dark red gum.
  • Macerated ethanol turmeric extract
  • the ethanol turmeric extract (51.4g) was separated by vacuum liquid chromatography (VLC) (Silica gel, 25Og, 230-400 mesh), eluting with hexane, dichloromethane / hexane (1-80%), dichloromethane, ethyl acetate / dichloromethane (1-40%), ethyl acetate, and ethanol to give 10 fractions (F 1 -F 10 ) on the basis of thin layer chromatography (TLC) analysis.
  • VLC vacuum liquid chromatography
  • Fraction Fi (2g) was further subjected to column chromatography (10Og of siliga gel 60, 70-230 mesh) eluting with hexane / acetone gradient solvent system, and ethanol to afford 9 fractions (Ai-A 9 ) on the basis of TLC analysis.
  • Fraction A 2 (114.4 mg) was then purified by medium pressure liquid chromatography (MPLC).
  • MPLC medium pressure liquid chromatography
  • a system disclosed in US Patent No. 6565745 can be used to perform the purification, eluting with hexane to yield ar-turmerone (26 mg, 0.0023% dry wt.).
  • Fraction F 3 was recrystallized with ethanol to provide curcumin (7.61 g, 0.66% dry wt.) as yellow crystals.
  • Fraction F 4 (4.74 g) was also separated by VLC (Silica gel, 200 g, 230-400 mesh), eluting with 0.1% methanol / dichloromethane to yield curcumin (670 mg, 0.058% dry wt).
  • curcuminoids the dry rhizomes of Curcuma longa (1.0 kg) were firstly extracted with hexane for 10 h by soxhlet extractor. The hexane solution was concentrated to dryness in a rotary evaporator to give hexane turmeric extract (53.75 g, 5.38% dry wt.) as a yellow oil. The residue was then extracted with ethyl acetate for 4Oh by soxhlet extractor. The ethyl acetate solution was concentrated, filtered and recrystallized with ethanol to give curcuminoids (32.76g, 3.28% dry wt) as orange crystals with melting point of 176-178 0 C. High-pressure liquid chromatography (HPLC) analysis of the orange crystals showed 86.5% curcumin (as shown in Fig. 2), 13.4% demethoxycurcumin, and 0.1% bisdemethoxycurcumin.
  • HPLC high-pressure liquid chromatography
  • the infrared (IR) spectra were obtained using a Fourier transform infrared spectrometer. Specifically, a Perkin-Elmer 2000 Fourier transform infrared spectrometer was used. Mass spectra (MS) were recorded on a mass spectrometer, such as AGILENT 1100 Series LC/MSB TRAP. Nuclear magnetic resonance (NMR) spectra were obtained using a NMR spectrometer system, specifically a VARIAN UNITY INOVA 400 (400 MHz for proton NMR ( 1 H NMR); 100 MHz for carbon- 13 NMR ( 13 C NMR)). Chemical shifts ( ⁇ ) values are expressed in parts per million (ppm) and coupling constant (J value) in Hz. Tetramethylsilane (TMS) was used as internal standard.
  • the spectroscopic data obtained for ar-turmerone is: colorless oil; 1 H NMR (400 MHz,
  • pharmaceutically acceptable carriers are added.
  • pharmaceutically acceptable carriers include starch, water, milk, sugar, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats, vegetable oils, gum, glycols or other known excipients.
  • Hemagglutinin assay was conducted to test the antiviral activity and viral protection property of Curcuma longa extracts.
  • the Curcuma longa extracts were diluted with solvents at concentrations of 0.0001ng/ml to 100,000 ng/ml.
  • An extract from each concentration was either incubated with 0.5% chicken red blood cells (rbc) for 30 minutes followed by addition of H5N1 AI virus-containing fluid or incubated with H5N1 AI virus containing fluid followed by addition of 0.5% chicken rbc suspension.
  • the hemagglutination of chicken rbc was examined. Inhibition of hemagglutination was detected as red dots of chicken rbc appearing at the bottom of the plate. This method was modified from the method by Swayne et al., 2003.
  • Curcuma longa extracts were determined using in vitro hemagglutination-inhibition assay.
  • the Curcuma longa extracts including hexane turmeric extract, ethyl acetate turmeric extract, 70% ethanol turmeric extract, ethanol turmeric extract, ar-turmerone, curcuminoids and pure curcumin were diluted with 1% dimethyl sulfoxide (DMSO) in phosphate buffer saline (PBS) at concentrations of 0.05ng/ml to 500ng/ml at ten fold dilution. The test was performed in a 96-well microplate.
  • DMSO dimethyl sulfoxide
  • PBS phosphate buffer saline
  • the H5N1 AI virus was isolated from infected chicken, inoculated in chicken eggs and the amniotic fluid from the infected chicken embryos was collected. Verification of H5N1 AI virus strain in the amniotic fluid was conducted using polymerase chain reaction (PCR).
  • H5N1 AI virus was serially diluted ten fold with 10OmM PBS and subsequently mixed with equal volume of 0.5% chicken red blood cells in PBS. The hemagglutination reaction was observed after 30 minutes of incubation at room temperature. The final concentration of H5N1 AI virus which had positive reaction to chicken rbc was used for following experiments.
  • the positive control for hemagglutination is the mixture of H5N1 AI virus with 0.5% chicken rbc and the negative control is the mixture of chicken rbc with 1% DMSO in PBS.
  • the inhibitory reaction of the Curcuma longa extracts was examined after 30 minutes. Inhibition of hemagglutination was detected as red dots of chicken rbc appearing at the bottom of the plate .
  • compositions, concentration of the curcuma extracts and the resultant numbers of wells showing positive hemagglutination of the anti-viral test are shown in Table 1 as provided below.
  • the number of wells showing positive hemagglutination reaction is inversely proportional to the extent of hemagglutination inhibition by the compound.
  • ar-turmerone was tested at 250ng/ml, 25ng/ml, 2.5ng/ml and 0.25ng/ml, no well showing positive hemagglutination was observed, indicating that ar-turmerone inhibited H5N1 AI viral hemagglutination in the anti-viral test. This shows that ar-turmerone demonstrates anti-viral activity.
  • curcuminoids and pure curcumin were tested, it was found that all wells showed positive hemagglutination reaction, thereby indicating that curcuminoids and pure curcumin do not inhibit hemagglutination and do not demonstrate any antiviral property.
  • the extracts were incubated with the chicken rbc for 30 minutes at room temperature followed by addition of 50 ⁇ l of H5N1 AI virus-containing fluid.
  • the positive control for hemagglutination is the mixture of H5N1 AI virus with 0.5% chicken rbc and the negative control is the mixture of chicken rbc with 1% DMSO in PBS.
  • the inhibitory reaction of the Curcuma longa extracts was examined after 30 minutes. Inhibition of hemagglutination was detected as red dots of chicken rbc appearing at the bottom of the plate.
  • compositions, concentration of the curcuma extracts and the resultant numbers of wells showing positive hemagglutination of the viral protection test are tabulated in Table 2a and 2b. Similar to the anti-viral test, the number of wells showing positive hemagglutination reaction is inversely proportional to the extent of hemagglutination inhibition by the compound. In the viral protection test, results have shown that four
  • Curcuma longa extracts namely hexane turmeric extract, ethyl acetate turmeric extract, 70% ethanol turmeric extract and ethanol turmeric extract, did not produce well showing positive reaction for hemagglutination, thereby demonstrating their abilities to protect chicken rbc from H5N1 AI viral hemagglutination after 30 minutes of incubation.
  • curcuminoids and curcumin were examined, all wells demonstrated positive hemagglutination reaction.
  • curcuminoids and curcumin do not posses viral protection property.
  • Singh G Singh O P and Maurya S. Chemical and biocidal investigations on essential oils of some Indian Curcuma species. Prog. Crystal Growth and Charact. 2002; 45; 75- 81.
  • Pirrung M C Morehead A T Jr. A sesquidecade of sesquiterpenes; Total Synthesis, 1980-1994. Part A: Acyclic and Monocyclic Sesquiterpens. In The Total Synthesis of Natural Products; Goldsmith D, Ed; John Wisley: New York. 1997; 10; 29-44.
  • the neuraminidase inhibitor GS4104 (oseltamivir phosphate) is efficacious against A/Hong Kong/ 156/97 (H5N1) and A/Hong Kong/ 1074/99 (H9N2) influenza viruses.

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Abstract

La présente invention concerne une composition pour inhiber l’interaction entre un virus et une cellule cible. La composition comprend une turmérone. Les turmérones peuvent comprendre l’arturmérone, la α-turmérone et la β-turmérone. Il est démontré en outre que des extraits de Curcuma longa qui contiennent des turmérones présentent un effet inhibiteur sur l’interaction d’un virus et d’une cellule cible. La présente invention concerne une procédure ou un procédé pour extraire la turmérone de Curcuma longa. La composition pour inhiber l’interaction entre un virus et une cellule cible peut être utilisée pour lutter contre l’infection par le virus H5N1 AI et protéger un individu contre l’infection par le virus H5N1 AI. La composition peut également être mélangée avec des aliments pour poulet afin de protéger les poulets contre des virus tels que le virus H5N1 AI.
PCT/SG2008/000456 2008-11-29 2008-11-29 Inhibition de l’interaction d’un virus et d’une cellule cible WO2010062260A1 (fr)

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KR1020117014890A KR101515822B1 (ko) 2008-11-29 2008-11-29 바이러스와 타겟 세포의 상호작용 저해
PCT/SG2008/000456 WO2010062260A1 (fr) 2008-11-29 2008-11-29 Inhibition de l’interaction d’un virus et d’une cellule cible

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Cited By (7)

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US8765816B2 (en) 2009-04-09 2014-07-01 Cognition Therapeutics, Inc. Inhibitors of cognitive decline
US9192585B2 (en) 2009-07-31 2015-11-24 Cognition Therapeutics, Inc. Inhibitors of cognitive decline
US9499462B2 (en) 2011-02-02 2016-11-22 Cognition Therapeutics, Inc. Isolated compounds from turmeric oil and methods of use
US9796672B2 (en) 2014-01-31 2017-10-24 Cognition Therapeutics, Inc. Isoindoline compositions and methods for treating neurodegenerative disease
CN110724044A (zh) * 2019-10-28 2020-01-24 珠海安哲生物科技有限公司 一种芳姜黄酮对照品的制备方法
CN111603526A (zh) * 2020-06-10 2020-09-01 天长亿帆制药有限公司 一种复方银花解毒药物在制备抗病毒药物中的应用
US11214540B2 (en) 2017-05-15 2022-01-04 Cognition Therapeutics, Inc. Compositions for treating neurodegenerative diseases

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9365491B2 (en) 2009-04-09 2016-06-14 Cognition Therapeutics, Inc. Inhibitors of cognitive decline
US8765816B2 (en) 2009-04-09 2014-07-01 Cognition Therapeutics, Inc. Inhibitors of cognitive decline
US9815770B2 (en) 2009-07-31 2017-11-14 Cognition Therapeutics, Inc. Inhibitors of cognitive decline
US9192585B2 (en) 2009-07-31 2015-11-24 Cognition Therapeutics, Inc. Inhibitors of cognitive decline
US9499462B2 (en) 2011-02-02 2016-11-22 Cognition Therapeutics, Inc. Isolated compounds from turmeric oil and methods of use
US10207991B2 (en) 2014-01-31 2019-02-19 Cognition Therapeutics, Inc. Isoindoline compositions and methods for treating neurodegenerative disease
US9796672B2 (en) 2014-01-31 2017-10-24 Cognition Therapeutics, Inc. Isoindoline compositions and methods for treating neurodegenerative disease
US10611728B2 (en) 2014-01-31 2020-04-07 Cognition Therapeutics, Inc. Isoindoline compositions and methods for treating neurodegenerative disease
US11691947B2 (en) 2014-01-31 2023-07-04 Cognition Therapeutics, Inc. Isoindoline compositions and methods for treating neurodegenerative disease
US11214540B2 (en) 2017-05-15 2022-01-04 Cognition Therapeutics, Inc. Compositions for treating neurodegenerative diseases
US11981636B2 (en) 2017-05-15 2024-05-14 Cognition Therapeutics, Inc. Compositions for treating neurodegenerative diseases
CN110724044A (zh) * 2019-10-28 2020-01-24 珠海安哲生物科技有限公司 一种芳姜黄酮对照品的制备方法
CN111603526A (zh) * 2020-06-10 2020-09-01 天长亿帆制药有限公司 一种复方银花解毒药物在制备抗病毒药物中的应用

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