WO2001064716A1 - Composes antiviraux - Google Patents

Composes antiviraux Download PDF

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Publication number
WO2001064716A1
WO2001064716A1 PCT/JP2001/001642 JP0101642W WO0164716A1 WO 2001064716 A1 WO2001064716 A1 WO 2001064716A1 JP 0101642 W JP0101642 W JP 0101642W WO 0164716 A1 WO0164716 A1 WO 0164716A1
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Prior art keywords
amino acid
compound
group
pharmaceutically acceptable
lys
Prior art date
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PCT/JP2001/001642
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English (en)
Japanese (ja)
Inventor
Nobutaka Fujii
Hideki Nakashima
Original Assignee
Nobutaka Fujii
Hideki Nakashima
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nobutaka Fujii, Hideki Nakashima filed Critical Nobutaka Fujii
Priority to AU2001236065A priority Critical patent/AU2001236065A1/en
Publication of WO2001064716A1 publication Critical patent/WO2001064716A1/fr

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04Linear peptides containing only normal peptide links
    • C07K7/08Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02Linear peptides containing at least one abnormal peptide link
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Definitions

  • the present invention has an excellent antiviral activity by acting as an antagonist against a novel antiviral compound, specifically, a glycoprotein, particularly a CXCR4 chemokine receptor, and has improved in vivo stability. It relates to a peptidic compound. Furthermore, the present invention relates to an anti-HIV agent containing the antiviral compound as an active ingredient. Background art
  • Polypeptides derived from captogae (genus Tachypleus, Limulus, Carcinoscopius), which have strong affinity for endotoxin, have five structural analogs, each consisting of 17 or 18 natural amino acids It is a polypeptide having a cyclic structure, and it has been known that these polypeptides have antibacterial activity (Matsuzaki K., Biochem. Biophys. Acta 1070, 259-264 (1991)).
  • WO90 / 043474 focuses on the strong endotoxin affinity of the Limulus aegypti polypeptide and discusses its structural transformation and anti-human immunodeficiency virus (HIV) activity, especially HIV A study of the correlation with the receptor describes that a novel polypeptide having high anti-disease activity was obtained.
  • HIV immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • HIV human immunodeficiency virus
  • the CXCR4 chemokine receptor has attracted attention, and it has become clear that the polypeptide is a peptide antagonist of the CXCR4 chemokine receptor (Tamamura H. et al., Biochem. Biophys. Res. Coraraun. 253, 877-882 (1998)).
  • the polypeptides disclosed in the prior art are composed of natural amino acids, (i) the terminal amino acid is degraded by endopeptidase, and (ii) the disulfide bond in the polypeptide molecule under reducing conditions. Is cut off, and (iii) poly
  • stability problems such as the turn part of the peptide being susceptible to protease-induced ⁇
  • reduction in the molecular weight of the peptide was required for the purpose of improving activity and reducing toxicity (Arakaki R. et al., J. Virology 73, 2, p. 1719-1723 (1999)). Disclosure of the invention
  • An object of the present invention is to provide an antiviral compound having a low molecular weight and an improved stability of the polypeptide.
  • the present invention provides a compound of formula (I):
  • X 2 is an amino acid having an aromatic ring
  • X 3 is a single bond or one CR—CH—, wherein is a hydrogen, C Cs alkyl or halogen atom;
  • X 4 is NHR 2 wherein R 2 is hydrogen or C Cs alkyl; or OH;
  • X 5 is one CH 2 —S—S—CH 2 —, or C 4 -C 8 a 7 ylene or C 4 -C 8 anolekenenylene;
  • Y 2 is an L-amino acid or a D-amino acid selected from Pro, A la, Va 1 or other aliphatic amino acids; and C it is L-citrulline;
  • the present invention also relates to an anti-HIV agent containing the ⁇ : virus compound as an active ingredient.
  • the peptide chain in the novel anti-disease compound of the present invention can be produced by a known method, for example, a solid phase synthesis method.
  • the carboxyl group of N-protected arginine may be bonded directly or, in some cases, via a spacer having a functional group capable of bonding to the carboxyl group or a carboxyl group to an insoluble resin having an amino group, to give each protected amino acid.
  • a spacer having a functional group capable of bonding to the carboxyl group or a carboxyl group to an insoluble resin having an amino group to give each protected amino acid.
  • the protecting group of the insoluble resin and the amino acid is removed to obtain the following formula ():
  • X 2 , X 3 , X 4 , Y and Y 2 are the same as those of the above formula (I)].
  • the canolepoxyl terminus of the amino acid residue at the C-terminus may be free (X 4 corresponds to -OH) or converted to an acid amide (X 4 corresponds to one NH 2 ) .
  • C 1 -C 5 alkyl can be added by a known method (X 4 corresponds to one NHR 2 ).
  • D-amino acids can be used in addition to L-amino acids.
  • the desired D-amino acid can be introduced by using the protected D-amino acid for solid phase synthesis.
  • the carboxyl group of the N-protected arginine at the C-terminal via the amino group or, optionally, the sugar group attached to the carboxyl group of the spacer is bonded.
  • It is an insoluble resin having an amino group, which is possible and can be removed thereafter.
  • resins include, for example, aminomethyl resin Fatty acid (aminomethinolelated styrene-dibutylbenzene copolymer), benzhydrylamine resin, methylbenzhydrylamine resin, dimethoxybenzhydrylamine (DMBHA) resin, aminomethylphenoxymethyl resin These derivatives are included.
  • methylbenzhydrylamine resin dimethoxybenzhydrylamine (DMBHA) resin, or aminomethylphenoxymethyl resin
  • aminomethyl resin is preferred in terms of yield .
  • the spacer having a hydroxyl group and a carpoxyl group capable of binding to a lipoxyl group include, but are not particularly limited to, those capable of converting a carboxyl group of arginine into a lipoxymethyl ester.
  • the protecting group for the amino group of the amino acid which can be used for the synthesis of the polypeptide chain in the compound of the present invention is, for example, t-butyloxycarbonyl (B oc) or 9-fluoroenylmethyloxycarbonyl. It is.
  • the protecting group for the arginine guanidino group is, for example, tosyl (To s), nitro, 4-methoxy-1,2,3,6-trimethylbenzene snorehoninole (Mtr) or 2,2,5,7,8-pentamethylchroman One is 6-snolehonyl (Pmc).
  • the protecting groups for the mercapto group of cysteine include, for example, benzyl (Bz1), 4-methoxybenzyl (MBz1), 4-methylbenzyl (41-MeBz1), acetamidomethyl (Acm), trityl (Tr t), force including 3-nitro-2-pyridinesulfenyl (Npys), t-butyl (t-Bu), t-butylthio (t-BuS), etc.
  • MBz1, 4-MeBz1 , Trt, Acm and Npys are preferred.
  • Hydroxyl group of tyrosine for example B z 1, 2, 6- dichloro port base Njiru (C 1 2 ⁇ B zl) , may not force ⁇ or protected protected with t-Bu.
  • Protecting groups for the ⁇ -amino group of lysine are, for example, benzyloxycarponyl ( ⁇ ), 2-chlorobenzoyl canoprene (C 1 ⁇ Z), Boc or Npys. It is preferable that each protecting group is appropriately selected in consideration of the peptide synthesis conditions and the like.
  • the binding of the protected amino acid can be carried out by a conventional condensation method such as DCC (diclohexyl canoleopreimide) method, DIP CDI (disopropyl carpoimide) method, active ester method, mixed or symmetric acid.
  • a conventional condensation method such as DCC (diclohexyl canoleopreimide) method, DIP CDI (disopropyl carpoimide) method, active ester method, mixed or symmetric acid.
  • Anhydrous method Carboerdiimidazole method, DC C-HOB t (1-hydroxybenzotriazole) method, Diphenyl phosphoryla
  • a zid method or the like a DCC method, a DCC-HOBt method, a DIPCDI method, and a symmetric acid anhydride method are preferred.
  • X 4 in formula (I), wherein 1 2 is a ⁇ 1 ⁇ 5 Arukiru] NHR 2 preferably is.
  • X 2 can be tributophan (X 6 is [TRP]), but tryptophan 1H-indole (TRP) can be replaced with Na 1, Cys (Bzl), Cys (Ad) or T rp (M ts) the substituted o; - by using amino acid peptidyl de synthesis, it is possible to obtain a desired X 2.
  • Formula (I) wherein —X 3 —Y 2 , preferably dLys-Pro or dLys—CH CH—Ala, where dLys represents D—lysine.
  • dLys-CH CH-A1a is more preferable because the stability of the compound is improved by making the turn portion of the i3 sheet structure of the compound of the present invention less susceptible to peptidase. .
  • a disulfide bond (X 5 is —CH 2 —S—S—CH 2 —) with cysteines at the 4- and 13-positions forms an S—S bridge, for example, via a mercapto group.
  • the mercapto group is protected with a protecting group t-BuS, and t-BuS is deprotected and oxidized to form a disulfide bond.
  • a known method can be used for the oxidation treatment, but usually an oxidizing agent such as oxygen in the air or a ferricyanate (eg, potassium ferricyanide) is used.
  • X 5 in the formula (I) is represented by the following general formula:
  • C 4 -C 8 alkylene or C 4 -C 8 alkenylene selected from the group consisting of pentamethylene, cis-3-pentenylene, trans-2-pentenylene or hexamethylene. preferable.
  • the derivative obtained in this way was subjected to conformation analysis by CD analysis, and it was shown that the compound derived from arylglycine and homoarylglycine had a ⁇ -sheet structure similar to that of the original peptide.
  • the compounds obtained as described above are subjected to extraction, recrystallization, various chromatographies (eg, gel filtration, ion exchange, partitioning, adsorption, reverse phase), electrophoresis, countercurrent partitioning, and other techniques.
  • Reversed phase high performance liquid chromatography which can be isolated and purified by methods known for peptides, is preferred.
  • the compounds represented by the formula (I) of the present invention are exemplified in Table 1 below.
  • the compounds ⁇ 134 and ⁇ 140 were prepared according to the prior art described above (Tamamura H. et al., Biochem. Biophys. Res. Coraraun. 253, 877-882 (1998); Arakaki R. et al. al., J. Virology 73, 2, p. 1719-1723 (1999)).
  • the antiviral compound of the present invention exemplified in this way has a high antiviral activity and a low toxicity equivalent to or higher than that of a known compound, and has improved stability in a living body.
  • In vivo stability is imparted because the peptide compound is less susceptible to aging and because the cyclic structure of the peptide compound is prevented from being linearized due to dissociation of the Z or SS bridge.
  • the drug containing the antiviral compound represented by the formula (I) of the present invention as an active ingredient contains the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and is used for virus infection or virus. It can be administered orally or parenterally for the disease.
  • the drug of the present invention can be formulated into various dosage forms, such as tablets, granules, capsules, powders, suppositories, pessaries, ointments, creams, aerosols, liquids, such as liquids for internal use, injections, and infusions. Can be administered.
  • various pharmaceutically acceptable additives may be used, for example, excipients, binders, disintegrants, buffers, dissolution aids, isotonic Agents, P-preservatives, antioxidants, pH regulators, suspending agents, diluents and the like.
  • the daily dose of the drug of the present invention varies depending on the method of administration, the dosage form and the degree of symptoms.
  • the antiviral compound of the present invention or a pharmaceutically acceptable salt thereof is administered in a range from 0.1 mg / kg to human LOOOOmg / kg human body weight.
  • parenteral administration as an injection it is administered in the range of 0.1 to 100 mg / kg human body weight.
  • the daily dose of the agent of the present invention can be administered one or more times, but more generally, once to three times a day, a unit dose is orally or parenterally administered. Is preferred. BEST MODE FOR CARRYING OUT THE INVENTION
  • a polypeptide having NH 2 -Arg-Arg-Trp-Cis-Tyr-Arg-Lys-Dlys-Pro-Tyr-Arg-Cit-Cys-Arg-C00H was synthesized as follows.
  • a peptide chain is constructed by a Ru-catalyzed RCM reaction according to the following reaction scheme 2, and hexamethylene is introduced to introduce the cyclic peptide of the present invention.
  • the active compounds TM14 ⁇ , ⁇ (E), TM140, HH (Z) and TM140, HH (Red) were synthesized.
  • TM140, AH (E), TMl40, AH (Z), TM140, AA (E), TMl40, HA (E), TMl40, HA (Z), TMl40, AH (Red ) And TMl40, AA (Red) were synthesized and CD analysis was performed with T140 synthesized in Reference Example 2. The results showed that the compound of the present invention had a sheet structure similar to that of T140 (FIG. 1).
  • test compound solution final concentration: 10 ⁇ M
  • test compound solution final concentration: 10 ⁇ M
  • 40 ⁇ L 3 OmM
  • hSDF ligand
  • the inhibition rate of each test compound with respect to the change in Ca 2+ concentration in the Vehic 1e-added group is calculated, and the compound concentration at which 50 % inhibition is exhibited is defined as IC 50 .
  • Table 5 shows the results.
  • Fmoc-DLy s (CIZ) was synthesized using an EAD I ((E) -alkene dipeptide isostere) synthesis method utilizing a stereospecific anti-SN 2 'reaction with an organocopper reagent.
  • E) CH CH] —A 1a was synthesized.
  • the antiviral activity against HIV of the compounds prepared in Examples 1 to 3 was determined as follows according to the MTT method (Pauwels et al., J. Virol. Methods, 20; 309-321 (1988)). .
  • HIV-infected MT-4 cells (2.5 10 4 cells / well, multiplicity of infection [MO1: 0.01]) were added with various concentrations of the test substance immediately after infection. After 5 days of culture at 37 ° C for at C0 2 incubator, it was measured number of remaining cells by MT T method. Antiviral activity, cell failure 50% inhibition concentration by HI V infection: expressed by (EC 5. 50% Effective Concentration ). On the other hand, in order to examine the cytotoxicity of the test compound to MT-4 cells, non-virus-infected cells were similarly cultured with various concentrations of the test substance. Cytotoxicity 50% cytotoxicity concentration by the test substance: expressed by (CC 5. 50% Cytotoxic Concentration ). The effective coefficient (SI: Selectivity Index) was calculated as CC 50 ZE C 50 .
  • SI Selectivity Index
  • a novel antiviral compound having excellent antiviral activity against human immunodeficiency virus (HIV) and improved in vivo stability or a pharmaceutically acceptable salt thereof, and An anti-HIV agent containing the active ingredient as an active ingredient is provided.
  • FIG. 1 is a graph of the CD analysis pattern of the compound of the present invention, showing the CD spectrum of the TM140 derivative from 80 to 260 nm.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Virology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne de nouveaux composés antiviraux représentés par la formule générale (I), lesquels composés possèdent une excellente activité antivirale et une stabilité que l'on améliore in vivo. L'invention concerne également des sels pharmaceutiquement acceptables desdits composés, ainsi que des agents anti-VIH renfermant lesdits composés comme principe actif.
PCT/JP2001/001642 2000-03-03 2001-03-02 Composes antiviraux WO2001064716A1 (fr)

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AU2001236065A AU2001236065A1 (en) 2000-03-03 2001-03-02 Antiviral compounds

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JP2000059495 2000-03-03

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020561A1 (fr) * 2000-09-05 2002-03-14 Seikagaku Corporation Nouveaux polypeptides et medicaments anti-vih contenant lesdits polypeptides
US8410059B2 (en) 2002-08-27 2013-04-02 Biokine Therapeutics Ltd. CXCR4 antagonist and use thereof
US8435939B2 (en) 2000-09-05 2013-05-07 Biokine Therapeutics Ltd. Polypeptide anti-HIV agent containing the same
US8455450B2 (en) 2006-12-21 2013-06-04 Biokine Therapeutics Ltd. Methods for obtaining a therapeutically effective amount of hematopoietic precursor cells and long term engraftment thereof
US9427456B2 (en) 2009-06-14 2016-08-30 Biokine Therapeutics Ltd. Peptide therapy for increasing platelet levels
US9439942B2 (en) 2012-04-24 2016-09-13 Biokine Therapeutics Ltd. Peptides and use thereof in the treatment of large cell lung cancer
WO2020101032A1 (fr) * 2018-11-16 2020-05-22 味の素株式会社 Procédé de production d'un peptide cyclisé ayant une liaison intramoléculaire s-s
US10682390B2 (en) 2015-07-16 2020-06-16 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US10993985B2 (en) 2016-02-23 2021-05-04 BioLmeRx Ltd. Methods of treating acute myeloid leukemia

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01153699A (ja) * 1987-12-11 1989-06-15 Takeda Chem Ind Ltd 新規ペプチドおよびその製造法
EP0425212A2 (fr) * 1989-10-23 1991-05-02 Smithkline Beecham Corporation Peptides cycliques à activité anti-aggrégante

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01153699A (ja) * 1987-12-11 1989-06-15 Takeda Chem Ind Ltd 新規ペプチドおよびその製造法
EP0425212A2 (fr) * 1989-10-23 1991-05-02 Smithkline Beecham Corporation Peptides cycliques à activité anti-aggrégante

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HIROKAZU TAMAMURA ET AL.: "A low-molecular-weight inhibitor against the chemokine receptor CXCR4: A strong anti-HIV peptide T140", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 253, 1998, pages 877 - 882, XP002937874 *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020561A1 (fr) * 2000-09-05 2002-03-14 Seikagaku Corporation Nouveaux polypeptides et medicaments anti-vih contenant lesdits polypeptides
US7138488B2 (en) 2000-09-05 2006-11-21 Biokine Therapeutics Ltd. Polypeptides having anti-HIV activity and compositions comprising same
US7595298B2 (en) 2000-09-05 2009-09-29 Biokine Therapeutics Ltd. Polypeptides having anti-HIV activity and compositions comprising same
US8435939B2 (en) 2000-09-05 2013-05-07 Biokine Therapeutics Ltd. Polypeptide anti-HIV agent containing the same
US8410059B2 (en) 2002-08-27 2013-04-02 Biokine Therapeutics Ltd. CXCR4 antagonist and use thereof
US8455450B2 (en) 2006-12-21 2013-06-04 Biokine Therapeutics Ltd. Methods for obtaining a therapeutically effective amount of hematopoietic precursor cells and long term engraftment thereof
US8663651B2 (en) 2006-12-21 2014-03-04 Biokine Therapeutics Ltd. T-140 peptide analogs having CXCR4 super-agonist activity for immunomodulation
US8765683B2 (en) 2006-12-21 2014-07-01 Biokine Therapeutics Ltd. T-140 peptide analogs having CXCR4 super-agonist activity for cancer therapy
US9427456B2 (en) 2009-06-14 2016-08-30 Biokine Therapeutics Ltd. Peptide therapy for increasing platelet levels
US9439942B2 (en) 2012-04-24 2016-09-13 Biokine Therapeutics Ltd. Peptides and use thereof in the treatment of large cell lung cancer
US11612638B2 (en) 2015-07-16 2023-03-28 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US11596666B2 (en) 2015-07-16 2023-03-07 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US10786547B2 (en) 2015-07-16 2020-09-29 Biokine Therapeutics Ltd. Compositions, articles of manufacture and methods for treating cancer
US11648293B2 (en) 2015-07-16 2023-05-16 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US11642393B2 (en) 2015-07-16 2023-05-09 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US11534478B2 (en) 2015-07-16 2022-12-27 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US11554159B2 (en) 2015-07-16 2023-01-17 Blokine Therapeutics Ltd. Compositions and methods for treating cancer
US11559562B2 (en) 2015-07-16 2023-01-24 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US11590200B2 (en) 2015-07-16 2023-02-28 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US10682390B2 (en) 2015-07-16 2020-06-16 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US11607444B2 (en) 2015-07-16 2023-03-21 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US11638743B2 (en) 2015-07-16 2023-05-02 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US11638742B2 (en) 2015-07-16 2023-05-02 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US10993985B2 (en) 2016-02-23 2021-05-04 BioLmeRx Ltd. Methods of treating acute myeloid leukemia
WO2020101032A1 (fr) * 2018-11-16 2020-05-22 味の素株式会社 Procédé de production d'un peptide cyclisé ayant une liaison intramoléculaire s-s
JPWO2020101032A1 (ja) * 2018-11-16 2021-10-07 味の素株式会社 分子内s−s結合を有する環化ペプチドの製造方法
US11939404B2 (en) 2018-11-16 2024-03-26 Ajinomoto Co., Inc. Method for producing cyclized peptide having intramolecular S-S bond
JP7476798B2 (ja) 2018-11-16 2024-05-01 味の素株式会社 分子内s-s結合を有する環化ペプチドの製造方法

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