WO2015080358A1 - Peptide de cryoconservation d'ovaire et composition le comprenant - Google Patents

Peptide de cryoconservation d'ovaire et composition le comprenant Download PDF

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Publication number
WO2015080358A1
WO2015080358A1 PCT/KR2014/004285 KR2014004285W WO2015080358A1 WO 2015080358 A1 WO2015080358 A1 WO 2015080358A1 KR 2014004285 W KR2014004285 W KR 2014004285W WO 2015080358 A1 WO2015080358 A1 WO 2015080358A1
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WIPO (PCT)
Prior art keywords
peptide
composition
ovary
cryopreservation
lycopene
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PCT/KR2014/004285
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English (en)
Korean (ko)
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김상재
김미란
Original Assignee
주식회사 카엘젬백스
김상재
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Publication of WO2015080358A1 publication Critical patent/WO2015080358A1/fr

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
    • A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof

Definitions

  • the present invention relates to a peptide having an effect of improving the survival rate of the ovary during ovarian cryopreservation and a composition comprising the same. More specifically, the present invention relates to a peptide derived from telomerase. It relates to a peptide having an effect of improving the survival rate and a composition comprising the same.
  • Ovarian cryopreservation is performed to prevent damage to the ovary that is active in cells due to chemotherapy and radiation treatments that cancer patients receive, and it can be performed before chemotherapy to regain the chance of pregnancy without loss of fertility after chemotherapy. This is a useful way. Specifically, in vitro culture of freeze-thawed ovarian tissue to obtain mature eggs [Hartshorne GM, Rev Reprod, 2: 94-104, 1997], or ovarian tissue to transplant homologous or heterologous individuals to obtain mature eggs.
  • ovarian cryopreservation has the problem that ovarian tissue may be damaged during the freeze-thaw process. This problem specifically implies that cellular physiology, cell membranes, and organelles are damaged by cryoprotectants, rapid temperature changes or osmotic pressure differences [Fuller BJ et al, Cryobiology, 26: 333-40, 1989].
  • An object according to an aspect of the present invention is to provide a composition having an effect of improving the survival rate of the ovary during ovarian cryopreservation.
  • a peptide comprising the amino acid sequence of SEQ ID NO: 1, a peptide having a sequence homology of 80% or more with the amino acid sequence or a peptide thereof; And at least one useful ingredient selected from the group consisting of lycopene is provided.
  • the fragment may be a fragment consisting of three or more amino acids.
  • the composition may comprise the peptide and lycopene simultaneously.
  • the lycopene may be extracted from tomatoes.
  • the composition may be to reduce the concentration of LDH (Lactate Dehydrogenase).
  • LDH Lacate Dehydrogenase
  • composition in the composition according to one aspect of the invention, can be used for pharmaceutical use.
  • a ovarian cryopreservation method comprising the step of treating the above-mentioned composition for cryopreservation of the ovary in a medium freezing the ovary and thawing it.
  • the ovary cryopreservation method may include embryo cryopreservation or egg cryopreservation.
  • the present invention may be provided a composition that can effectively improve the survival rate of the ovary during ovarian cryopreservation.
  • the present invention is expected to increase gradually.
  • 1 is a graph measuring the LDH concentration at 2, 4, 6, and 8 days of each medium after undergoing freeze-thaw of the ovary and treating each medium with Pep1 and lycopene.
  • Figure 2 is a graph of measuring the LDH concentration at 2, 4, 6, 8 days of each medium after the ovary freeze-thaw process, and treated with Pep1, lycopene and Pep1 and lycopene in each medium to be.
  • Figure 3 is a graph measuring the LDH concentration at 2 days, 4 days, 6 days after treatment of 50 ⁇ mol and 100 ⁇ mol Pep1 in ovarian tissue medium.
  • the present invention may be variously modified and may have various embodiments.
  • the present invention will be described in more detail. However, this is not intended to limit the present invention to specific embodiments, it should be understood to include all transformations, equivalents, and substitutes included in the spirit and scope of the present invention.
  • the detailed description of the related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted.
  • Telomere is a genetic material repeatedly present at the end of a chromosome and is known to prevent damage to the chromosome or binding to another chromosome. Each time a cell divides, the telomeres become slightly shorter. After a certain number of cell divisions, the telomeres become very short, and the cells stop dividing and die. On the other hand, elongation of telomeres is known to prolong cell life. For example, cancer cells secrete an enzyme called telomerase, which prevents telomeres from shortening, so that cancer cells can continue to proliferate without dying.
  • Lycopene is a natural product found mainly in tomatoes and is a powerful antioxidant.
  • Lycopene's inhibitory action on carcinogenesis and mutagenesis has been shown to reduce reactive oxygen species scavenging and upregulation of alcoholism detoxification [Astorg P, Nutrition Cancer 29, 60-68, 1997]. , Inhibition of cell cycle degeneration and regulation of signal transduction pathways [Bhuvaneswari, V, Current Medical Chemistry Anticancer Agents 5, 627-635, 2005]. Recently, it has been shown that lycopene has the ability to prevent chemically induced primary DNA damage and chromosomal cleavage and loss of ovarian cells in Chinese hamsters [Scolastici C et al, Toxicology in Vitro 21, 841, 2007].
  • Peptides disclosed herein can include peptides having a sequence of SEQ ID NO: 1 or a peptide that is a fragment of sequence of SEQ ID NO: 1 and a peptide having at least 80%, at least 85%, at least 90%, or at least 95% sequence homology. Can be.
  • a peptide of SEQ ID NO: 1, a peptide that is a fragment of SEQ ID NO: 1, or a peptide having a sequence homology of at least 80% with the peptide sequence is used in telomerase, specifically in human ( Homo sapiens ) telomerase. Peptides derived.
  • Peptides disclosed herein can include peptides having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% homology.
  • the peptides disclosed herein, peptides or fragments thereof comprising SEQ ID NO: 1 and one or more amino acids, two or more amino acids, three or more amino acids, four or more amino acids, five or more amino acids, six or more amino acids Or peptides with seven or more amino acids changed.
  • the cell penetrating peptide may consist of up to 30 amino acids.
  • cell penetrating peptides include telomerases, specifically peptides derived from human ( Homo sapiens ) telomerase.
  • the peptide described in SEQ ID NO: 1 is shown in Table 1 below.
  • the "name” in Table 1 below is to distinguish peptides.
  • the peptide set forth in SEQ ID NO: 1 represents the entire peptide of human telomerase.
  • a peptide having a sequence of SEQ ID NO: 1, a peptide that is a fragment of SEQ ID NO: 1, or a peptide having at least 80% sequence homology with the peptide sequence corresponds to a peptide included in telomerase.
  • synthetic peptides selected and synthesized at the positional peptides.
  • SEQ ID 2 shows the amino acid sequence of the entire telomerase.
  • amino acid changes belong to a property that allows the physicochemical properties of the peptide to be altered.
  • amino acid changes can be made, such as improving the thermal stability of the peptide, altering substrate specificity, changing the optimal pH, and the like.
  • amino acid includes not only the 22 standard amino acids that are naturally incorporated into the peptide, but also D-isomers and modified amino acids. Accordingly, in one aspect of the invention the peptide may be a peptide comprising D-amino acids. Meanwhile, in another aspect of the present invention, the peptide may include a non-standard amino acid or the like which has been post-translational modified.
  • post-translational modifications include phosphorylation, glycosylation, acylation (including, for example, acetylation, myristoylation and palmitoylation), alkylation ), Carboxylation, hydroxylation, glycation, biotinylation, ubiquitinylation, changes in chemical properties (e.g., beta-elimination deimidization) , Deamidation) and structural changes (eg, formation of disulfide bridges). It also includes changes in amino acids, such as changes in amino groups, carboxy groups or side chains, caused by chemical reactions that occur during the linkage with crosslinkers to form peptide conjugates.
  • Peptides disclosed herein can be wild-type peptides identified and isolated from a natural source.
  • a peptide disclosed herein may be an artificial variant, comprising an amino acid sequence in which one or more amino acids are substituted, deleted, and / or inserted as compared to a peptide that is SEQ ID NO: 1 or a fragment thereof.
  • Amino acid changes in the wild type polypeptide as well as in artificial variants include conservative amino acid substitutions that do not significantly affect the folding and / or activity of the protein.
  • conservative substitutions include basic amino acids (arginine, lysine and histidine), acidic amino acids (glutamic acid and aspartic acid), polar amino acids (glutamine and asparagine), hydrophobic amino acids (leucine, isoleucine, valine and methionine), aromatic amino acids (phenylalanine, Tryptophan and tyrosine), and small amino acids (glycine, alanine, serine and threonine). Amino acid substitutions that generally do not alter specific activity are known in the art.
  • the most common exchanges are Ala / Ser, Val / Ile, Asp / Glu, Thr / Ser, Ala / Gly, Ala / Thr, Ser / Asn, Ala / Val, Ser / Gly, Tyr / Phe, Ala / Pro, Lys / Arg, Asp / Asn, Leu / Ile, Leu / Val, Ala / Glu, and Asp / Gly, and vice versa.
  • Other examples of conservative substitutions are shown in the following table.
  • residue substitution Ala (A) val; leu; ile Val Arg (R) lys; gln; asn Lys Asn (N) gln; his; asp, lys; arg Gln Asp (D) glu; asn Glu Cys (C) ser; ala Ser Gln (Q) asn; glu Asn Glu (E) asp; gln Asp Gly (G) Ala Ala His (H) asn; gln; lys; arg Arg Ile (I) leu; val; met; ala; phe; norleucine Leu Leu (L) norleucine; ile; val; met; ala; phe Ile Lys (K) arg; gln; asn Arg Met (M) leu; phe; ile Leu Phe (F) leu; val; ile; ala; tyr Tyr
  • composition comprising a peptide comprising the amino acid sequence of SEQ ID NO: 1 (comprising), a peptide having a sequence homology of 80% or more with the amino acid sequence or a fragment thereof peptide as an active ingredient to provide.
  • the composition for cryopreservation of the ovary comprises a peptide comprising an amino acid sequence of SEQ ID NO: 1 in one aspect, a peptide having a sequence homology of 80% or more with the amino acid sequence, or a fragment thereof. It may be included in the content of mg / L to 1000 mg / L, specifically 10 mg / L to 500 mg / L, more specifically 30 mg / L to 200 mg / L, but if the difference in effect depending on the dose It can be adjusted appropriately. When included in the above range or less, it is not only appropriate to exhibit the intended effect of the present invention, but also satisfies both the stability and safety of the composition, it may be appropriate to include in the above range in terms of cost-effectiveness. .
  • composition according to one aspect of the present invention can be applied to all animals including humans, dogs, chickens, pigs, cattle, sheep, guinea pigs or monkeys.
  • the composition is for ovarian cryopreservation comprising as an active ingredient a peptide comprising the amino acid sequence of SEQ ID NO: 1, a peptide having a sequence homology of 80% or more with the amino acid sequence or a fragment thereof It provides a pharmaceutical composition.
  • the pharmaceutical composition according to one aspect of the present invention may be administered orally, rectal, transdermal, intravenous, intramuscular, intraperitoneal, intramedullary, intradural or subcutaneous.
  • Formulations for oral administration may be, but are not limited to, tablets, pills, soft or hard capsules, granules, powders, solutions or emulsions.
  • Formulations for parenteral administration may be, but are not limited to, injections, drops, lotions, ointments, gels, creams, suspensions, emulsions, suppositories, patches or sprays.
  • compositions according to one aspect of the invention may include additives such as diluents, excipients, lubricants, binders, disintegrants, buffers, dispersants, surfactants, colorants, flavoring or sweetening agents as needed.
  • additives such as diluents, excipients, lubricants, binders, disintegrants, buffers, dispersants, surfactants, colorants, flavoring or sweetening agents as needed.
  • Pharmaceutical compositions according to one aspect of the invention may be prepared by conventional methods in the art.
  • Preferred embodiments of the invention include the most optimal mode known to the inventors for carrying out the invention. Variations of the preferred embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to make appropriate use of such variations, and the inventors expect the invention to be practiced in a manner different from that described herein. Accordingly, the invention includes all modifications and equivalents of the subject matter referred to in the appended claims, as permitted by patent law. Moreover, any combination of the abovementioned elements within all possible variations is included in the invention unless expressly stated to the contrary or apparently contradictory in context. While the invention has been particularly shown and described with reference to exemplary embodiments, those skilled in the art will understand that various changes in form and detail may be made without departing from the spirit and scope of the invention as defined by the following claims .
  • the peptide of SEQ ID NO: 1 was prepared according to the conventionally known solid peptide synthesis method. Specifically, peptides were synthesized by coupling amino acids from the C-terminus one by one through Fmoc solid phase peptide synthesis (SPPS) using ASP48S (Peptron, Inc., Daejeon, Korea). As follows, the first amino acid at the C-terminus of the peptides was attached to the resin. For example:
  • Coupling reagent is HBTU [2- (1H-Benzotriazole-1-yl) -1,1,3,3-tetamethylaminium hexafluorophosphate] / HOBt [N-Hydroxxybenzotriazole] / NMM [4-Methylmorpholine] It was. Fmoc removal was performed using piperidine in DMF in 20% of DMF.
  • Each peptide was synthesized by repeating a process of reacting the amino acids with each other, washing with a solvent, and then deprotecting the amino acid using the state in which the amino acid protecting group was bound to the solid support.
  • the synthesized peptide was separated from the resin and then purified by HPLC, and confirmed by MS and lyophilized. The purity of all peptides used in the experiment was 95% or higher, which was determined using high-performance liquid chromatography.
  • Lactate dehydrogenase is an enzyme found in animals, plants and prokaryotes. LDH is found in many somatic cells, such as blood cells and myocardium, and is important because it is released when tissue damage occurs and can be used as a marker of injury or disease.
  • LDH assays were performed on Pep1 and lycopene to derive basic data to characterize Pep1's inhibition of LDH released during ovarian freeze-thaw.
  • Ovarian medulla is scraped off with a surgical knife to remove it, leaving only the ovarian cortex as much as possible. After washing with DPBS, transfer to a culture dish containing DPBS, and then cut the ovary with a surgical knife. 1 mm x 5 mm x 1 mm).
  • Pep1 ((10% SPS + 1 IU / ml HMG + Pep1 (Cat. No., Kaelgemvax, S. Korea) 100 ⁇ mol)
  • Lycopene ((10% SPS + 1 IU / ml HMG + Lycopene (Cat.No. L9879, Sigma, U.S.A.) 10 ⁇ mol)
  • the results of Experiment 1 showed that the lycopene-treated group had lower LDH concentration than the control group, and that the Pep 1-treated group had lower LDH concentration than the lycopene-treated group at each measurement point from 2 to 8 days. It could be confirmed (see FIG. 1).
  • the group administered with Pep1 and lycopene showed lower LDH concentrations than the control group or the group administered with Pep1 and lycopene at each measurement point of 2 days, 4 days and 6 days (see FIG. 2).
  • the experimental results of the experimental group 3 showed that the LDH concentration was lower than that of the control group and the low concentration group (50 ⁇ mol) in the group treated with high concentration (100 ⁇ mol) of Pep1 at the 4th and 6th day of measurement. 3).

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Abstract

La présente invention concerne un peptide de cryoconservation d'un ovaire et une composition le comprenant. Plus spécifiquement, la présente invention concerne une composition comprenant un peptide dérivé de la télomérase et/ou du lycopène pour améliorer le taux de survie d'un ovaire pendant la congélation-décongélation de l'ovaire, ou la cryoconservation ou la greffe de l'ovaire. Selon la présente invention, il est possible de fournir une composition qui peut efficacement améliorer le taux de survie d'un ovaire durant la cryoconservation de l'ovaire. Dans la mesure où il est devenu important récemment de maintenir la fertilité, à cause de l'élévation du nombre de jeunes ayant survécu à un cancer et de l'élévation de l'âge moyen du mariage et du premier accouchement des femmes, il est prévu que l'utilité de la présente invention augmentera progressivement.
PCT/KR2014/004285 2013-11-29 2014-05-13 Peptide de cryoconservation d'ovaire et composition le comprenant WO2015080358A1 (fr)

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KR1020130147224A KR102106757B1 (ko) 2013-11-29 2013-11-29 난소 동결 보존용 펩티드 및 이를 포함하는 조성물
KR10-2013-0147224 2013-11-29

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1093381B1 (fr) * 1998-07-08 2003-08-20 GemVax AS Peptides antigenes derives de la telomerase
WO2005094576A2 (fr) * 2004-03-25 2005-10-13 Community Hospitals Of Indiana, Inc. Milieu de cryoconservation
US20090186335A1 (en) * 2006-05-30 2009-07-23 Palasz Andre T Method of preparing unilamellar vesicles for the cryopreservation and culture of germ cells and embryos
WO2013138239A1 (fr) * 2012-03-14 2013-09-19 Membrane Protective Technologies, Inc. Systèmes et substances pour la cryoconservation de cellules viables

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100976241B1 (ko) 2010-03-15 2010-08-17 (주)대덕바이오 알코올분해 및 숙취해소용 돌나물 분획물

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1093381B1 (fr) * 1998-07-08 2003-08-20 GemVax AS Peptides antigenes derives de la telomerase
WO2005094576A2 (fr) * 2004-03-25 2005-10-13 Community Hospitals Of Indiana, Inc. Milieu de cryoconservation
US20090186335A1 (en) * 2006-05-30 2009-07-23 Palasz Andre T Method of preparing unilamellar vesicles for the cryopreservation and culture of germ cells and embryos
WO2013138239A1 (fr) * 2012-03-14 2013-09-19 Membrane Protective Technologies, Inc. Systèmes et substances pour la cryoconservation de cellules viables

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
UYSAL ET AL.: "Effects of Oxidized Glutathione, Bovine Serum Albumin, Cysteine and Lycopene on the Quality of Frozen-Thawed Ram Semen", ACTA VETERINARIA BRNO, vol. 76, no. 3, 2007, pages 383 - 390 *

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KR20150062502A (ko) 2015-06-08
KR102106757B1 (ko) 2020-05-06

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