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WO2018182054A1 - Structure fonctionnelle d'acide nucléique et son procédé de préparation - Google Patents

Structure fonctionnelle d'acide nucléique et son procédé de préparation Download PDF

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Publication number
WO2018182054A1
WO2018182054A1 PCT/KR2017/003274 KR2017003274W WO2018182054A1 WO 2018182054 A1 WO2018182054 A1 WO 2018182054A1 KR 2017003274 W KR2017003274 W KR 2017003274W WO 2018182054 A1 WO2018182054 A1 WO 2018182054A1
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nucleic acid
base
amino acid
derived structure
acid construct
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Korean (ko)
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곽민석
안동준
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Pukyong National University
Korea University Research and Business Foundation
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Pukyong National University
Korea University Research and Business Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • 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
    • A01N1/10—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
    • A01N1/10—Preservation of living parts
    • A01N1/12—Chemical aspects of preservation
    • A01N1/122—Preservation or perfusion media
    • A01N1/126—Physiologically active agents, e.g. antioxidants or nutrients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23B—PRESERVATION OF FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES; CHEMICAL RIPENING OF FRUIT OR VEGETABLES
    • A23B2/00—Preservation of foods or foodstuffs, in general
    • A23B2/70—Preservation of foods or foodstuffs, in general by treatment with chemicals
    • A23B2/725—Preservation of foods or foodstuffs, in general by treatment with chemicals in the form of liquids or solids
    • A23B2/729—Organic compounds; Microorganisms; Enzymes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/13—Nucleic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K3/00—Materials not provided for elsewhere
    • C09K3/18—Materials not provided for elsewhere for application to surfaces to minimize adherence of ice, mist or water thereto; Thawing or antifreeze materials for application to surfaces
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K5/00—Heat-transfer, heat-exchange or heat-storage materials, e.g. refrigerants; Materials for the production of heat or cold by chemical reactions other than by combustion
    • C09K5/20—Antifreeze additives therefor, e.g. for radiator liquids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to nucleic acid constructs that inhibit the formation or growth of ice crystals.
  • the DNA information is encoded by adenine (A), guanine (G), cytosine (C) and thymine (T), which are base units of nucleotides.
  • A adenine
  • G guanine
  • C cytosine
  • T thymine
  • Single strands of DNA recognize and bind their complementary strands by hybridization (hybridization) to form double stranded nucleic acids. This can be caused by the formation of nucleic acid specific base pairs such that A recognizes T and G recognizes C. Due to these structural features, programmed self-assembleable DNA is considered to be a material with a variety of possibilities beyond the ability of biopolymers to store genetic information.
  • DNA structure manufacturing technology that assembles sequences and self-assembles into precise structure can design the complex structure we want in simple language and control the designed structure in a specific environment.
  • DNA compared to other materials is that in addition to the sophisticated functions and structural programming mentioned above, they are fundamentally biocompatible materials that exist in our bodies.
  • the DNA molecule itself is a polymer capable of biochemical and chemical synthesis and is fairly stable in vivo.
  • At least one base is a base having a threonine derived structure; At least one base is a base having a polar amino acid derived structure selected from the group consisting of serine, asparagine and glutamine, and at least one base is a base having a hydrophobic amino acid derived structure selected from the group consisting of alanine, isoleucine, leucine and valine , Nucleic acid construct.
  • nucleic acid construct of 1 above wherein the base having a polar amino acid-derived structure and the base having a hydrophobic amino acid-derived structure are located within 3 bp.
  • R is a residue of threonine; A is an integer from 1 to 5; And b is an integer of 0 to 5.
  • R is a residue of serine, asparagine or glutamine; A is an integer from 1 to 5; And b is an integer of 0 to 5.
  • R is a residue of alanine, isoleucine, leucine or valine; A is an integer from 1 to 5; And b is an integer of 0 to 5.
  • nucleic acid construct according to the above 1, wherein the nucleotide including the base having the threonine-derived structure is represented by the following Formula 2:
  • X is OH or H
  • B is adenine, thymine, guanine, cytosine or uracil
  • R is a residue of threonine.
  • nucleic acid construct according to 1 above wherein the nucleotide including the base having the polar amino acid-derived structure is represented by the following Formula 2:
  • X is OH or H
  • B is adenine, thymine, guanine, cytosine or uracil
  • R is a residue of serine, asparagine or glutamine.
  • nucleic acid construct according to the above 1, wherein the nucleotide including the base having the hydrophobic amino acid-derived structure is represented by Formula 2 below:
  • X is OH or H
  • B is adenine, thymine, guanine, cytosine or uracil
  • R is a residue of alanine, isoleucine, leucine or valine.
  • nucleic acid construct of 1 above wherein the nucleic acid construct comprises at least two nucleic acid single strands that are complementarily bound.
  • nucleic acid construct comprising at least two nucleic acid single strands complementarily bonded to each other, and at least one of the complementary bound bases is a base having a threonine-derived structure;
  • nucleic acid construct of 1 above wherein the nucleic acid construct is arranged such that at least one nucleic acid double strand comprises four first portions arranged in one direction.
  • nucleic acid construct of 1 above wherein the nucleic acid construct is arranged so that at least one nucleic acid double strand comprises six first portions arranged in one direction.
  • nucleic acid construct according to 1 above, wherein the nucleic acid construct comprises a base having at least two threonine derived structures; A nucleic acid construct comprising a base having at least two polar amino acid derived structures and a base having a hydrophobic amino acid derived structure, wherein the minimum spacing between the bases is 0.34 nm.
  • a method of making a nucleic acid construct comprising binding a plurality of nucleotides having a threonine derived structure, a polar amino acid derived structure or a hydrophobic amino acid derived structure bound to a base of at least one nucleotide.
  • a composition which inhibits the formation, growth or recrystallization of ice crystals comprising the nucleic acid constructs 1 to 15 above.
  • a biological sample preservative comprising the nucleic acid constructs 1 to 15 above.
  • the nucleic acid construct according to the present invention is a base having at least one base having a threonine derived structure; Since at least one base is a base having a structure derived from a polar amino acid and at least one base is a base having a structure derived from a hydrophobic amino acid, formation, growth or recrystallization of ice crystals can be suppressed.
  • the nucleic acid construct according to the present invention can be introduced directly into the position of the nucleic acid construct intact by using a modified base having a functional group, and thus the production method is simple.
  • nucleic acid construct according to the present invention is a biocompatible material, safety problems can be minimized and can be utilized in various fields.
  • Figure 1 shows a nucleic acid construct comprising a modified base having a threonine derived structure.
  • Figure 2 shows an example of binding a threonine derived structure to the base of the nucleotide.
  • FIG 3 shows an example of a nucleotide comprising a base having a threonine derived structure for application to an enzymatic synthesis method.
  • FIG. 4 shows a nucleic acid construct comprising a base having a threonine derived structure that interacts with ice.
  • FIG. 5 is a perspective view showing an example of a nucleic acid construct of the present invention.
  • FIG. 6 is a perspective view showing an example of a nucleic acid construct of the present invention.
  • FIG. 7 is a cross-sectional view showing an example of a nucleic acid construct of the present invention.
  • the present invention provides nucleic acid constructs wherein at least one base is a modified base having a functional group.
  • Nucleic acid constructs include oligonucleotides in which at least two single strands of nucleic acid are complementarily bound.
  • the nucleic acid constructs of the invention also include oligonucleotides in which the entirety of at least two nucleic acid single strands is complementarily linked or a portion of the nucleic acid single strand is complementarily bound. It is not necessary for each single strand of nucleic acid to have a sequence that is completely complementary to each other, and it is sufficient to have sufficient complementarity within a range capable of hybridizing with each other to maintain the structure of the desired nucleic acid.
  • modified base refers to a base having a functional group, not a natural base. Nucleotides that make up a nucleic acid consist of a combination of base-orthosaccharide-phosphate. For DNA, the base is one of adenine (A), guanine (G), cytosine (C), or thymine (T), and for RNA, adenine (A), guanine (Guanine). , G), cytosine (C), or uracil (U).
  • Modified base of the present invention refers to a functional group introduced into the base of the structure of the nucleotide.
  • the functional group of the modified base may be, for example, a functional group derived from an organic compound, a nanomaterial, an amino acid, or the like.
  • the present invention provides that at least one base is a base having a threonine derived structure; At least one base is a base having a polar amino acid derived structure selected from the group consisting of serine, asparagine and glutamine, and at least one base is a base having a hydrophobic amino acid derived structure selected from the group consisting of alanine, isoleucine, leucine and valine And nucleic acid constructs.
  • the amino acid-derived structure refers to a “residue” portion of hydrogen, a carboxyl grouop, an amino group, and a side chain bonded to alpha carbon based on alpha carbon in the amino acid basic skeleton.
  • the threonine-derived structure may be represented by the following formula (1).
  • R is a residue of threonine; a is an integer of 1 to 5; and b is an integer of 0 to 5.
  • the residue of threonine is to be.
  • the polar amino acid derived structure may be represented by the following formula (1).
  • R is a residue of serine, asparagine or glutamine; wherein a is an integer from 1 to 5; and b is an integer from 0 to 5.
  • the residue of serine is ,
  • the residue of asparagine is ,
  • the residue of glutamine is to be.
  • the hydrophobic amino acid-derived structure may be represented by the following formula (1).
  • R is a residue of alanine, isoleucine, leucine or valine; a is an integer from 1 to 5; and b is an integer from 0 to 5.
  • the residue of alanine is , The residue of isoleucine , The residue of leucine is , The residue of valine is to be.
  • Formula 1 may include a triple bond and a single bond to give the flexibility of the structure, by adjusting a and b in the formula (1) can adjust the flexibility and length of the structure.
  • the threonine derived structure is a threonine residue, Has The threonine residue has a hydroxyl group (-OH) capable of providing hydrogen bonds and a methyl group (-CH 3 ) capable of providing a hydrophobic surface, thus providing a hydrogen bond and at the same time providing a hydrophobic surface.
  • -OH hydroxyl group
  • -CH 3 methyl group
  • a base having at least one threonine derived structure if necessary, at least one of the remaining bases is a base having a polar amino acid derived structure selected from the group consisting of serine, asparagine and glutamine, and at least one base is alanine, It may be a base having a structure derived from hydrophobic amino acid selected from the group consisting of isoleucine, leucine and valine.
  • the polar amino acid derived structure has a residue of an amino acid selected from the group consisting of serine, asparagine and glutamine.
  • the residue of serine is ,
  • the residue of asparagine is ,
  • the residue of glutamine is to be. Since the residues of the serine, asparagine and glutamine have a hydroxyl group or an amino group (amino group, -NH 2 ), it can form a hydrogen bond with water.
  • the hydrophobic amino acid derived structure has residues of amino acids selected from the group consisting of alanine, isoleucine, leucine and valine.
  • the residue of alanine is , The residue of isoleucine ,
  • the residue of leucine is ,
  • the residue of valine is to be. Since the residues of alanine, isoleucine, leucine and valine contain only alkyl groups, they can provide a hydrophobic surface.
  • the base having the polar amino acid-derived structure and the base having the hydrophobic amino acid-derived structure may be located within 3 bp (base pair). Positioning the polar amino acid-derived structure and the hydrophobic amino acid-derived structure adjacently can suppress the formation, growth, or recrystallization of ice crystals. In order to suppress the formation, growth, or recrystallization of ice crystals, hydrogen bonds and hydrophobic surfaces capable of interacting with ice crystals are required at the same time. The same effect can be achieved by providing a functional group having a portion at the same time. Since the base having the threonine-derived structure provides both the hydrophobic portion and the polar portion, there is no limitation on the spacing between bases having the threonine-derived structure.
  • the threonine derived structure or the polar amino acid derived structure and the hydrophobic amino acid derived structure located within 3 bp have an effect of inhibiting the formation, growth or recrystallization of ice crystals.
  • the threonine derived structure can provide both hydrogen bonds and hydrophobic surfaces
  • the polar amino acid derived structures and hydrophobic amino acid derived structures located within 3 bp can provide hydrogen bonds and hydrophobic surfaces to interact with ice crystals, and microcrystalline It is possible to prevent the microcrystals from forming large crystals and to maintain the liquid state. Alternatively, recrystallization of ice crystals can be suppressed upon thawing.
  • the nucleotide including the modified base having the threonine-derived structure may be represented by the following formula (2).
  • X is OH or H
  • B is adenine, thymine, guanine, cytosine or uracil
  • R is a residue of threonine.
  • a nucleotide comprising a modified base having the polar amino acid-derived structure may be represented by the following formula (2).
  • X is OH or H
  • B is adenine, thymine, guanine, cytosine or uracil
  • R is a residue of serine, asparagine or glutamine.
  • the nucleotide including a modified base having the hydrophobic amino acid-derived structure may be represented by the following formula (2).
  • the nucleic acid construct of the present invention may comprise a nucleotide comprising a modified base having the threonine derived structure.
  • the nucleic acid construct of the present invention may include a nucleotide comprising a modified base having the polar amino acid-derived structure and a nucleotide comprising a modified base having the hydrophobic amino acid-derived structure.
  • the nucleic acid construct includes a plurality of nucleotides including a modified base having a threonine-derived structure; Or a plurality of nucleotides including a modified base having a polar amino acid derived structure and a hydrophobic amino acid derived structure and a plurality of nucleotides including a natural base.
  • the modified base may be positioned at a desired position in the nucleic acid construct.
  • the modified base having a threonine-derived structure, a polar amino acid-derived structure, or a hydrophobic amino acid-derived structure is a -BR moiety
  • B may be adenine, thymine, guanine, cytosine, or uracil, which are bases constituting the nucleic acid.
  • R is a threonine derived structure, a polar amino acid derived structure or a hydrophobic amino acid derived structure of formula (1).
  • R may be bonded to any atom constituting the base.
  • the pentose sugar when X is OH, the pentose sugar is a structure of ribose, and when X is H, the pentose sugar is a structure of deoxyribose. It is a sugar which constitutes RNA of ribose, and deoxyribose is a sugar which constitutes DNA.
  • the nucleic acid construct comprises at least two nucleic acid single strands that are complementarily bound, and at least one of the complementary bound bases is a base having a threonine derived structure; At least one base may be a base having a structure derived from a polar amino acid, and at least one base may have a base having a structure derived from a hydrophobic amino acid.
  • the portion comprising at least two nucleic acid single strands in the nucleic acid construct may be all or part of the nucleic acid construct.
  • Part of the nucleic acid construct may comprise a single strand of nucleic acid.
  • the nucleic acid construct comprises a base having at least two threonine derived structures; A base having at least two polar amino acid derived structures and a modified base having a hydrophobic amino acid derived structure, wherein the minimum spacing between the bases may be 0.34 nm.
  • the nucleic acid construct comprises a base having a threonine derived structure; A base having a polar amino acid derived structure and a base having a hydrophobic amino acid derived structure;
  • the minimum spacing between the bases comprising at least two double helices and located in each double helix may be 2.3 nm.
  • the present invention provides a method for producing a nucleic acid construct comprising binding a plurality of nucleotides having a threonine derived structure, a polar amino acid derived structure or a hydrophobic amino acid derived structure to a base of at least one nucleotide.
  • Joining the plurality of nucleotides may be performed by chemical or enzymatic methods. Depending on which method is applied, the precursor structure of the nucleotide comprising the modified base may vary.
  • nucleotide precursor including a modified base for binding the plurality of nucleotides by a chemical method is shown in Chemical Formula 3 below.
  • X is OH or H
  • B is adenine, thymine, guanine, cytosine or uracil
  • R is a threonine derived structure, a polar amino acid derived structure or a hydrophobic amino acid derived structure
  • DMT is 4,4'-dimethoxytrityl
  • CEPA is 2-cyanoethyl-N, N-diisopropylphosphoramidite
  • L represents a leaving group.
  • L may be, for example, halogen.
  • the polar amino acid-derived structure is specifically a residue of serine, asparagine or glutamine
  • the hydrophobic amino acid-derived structure is specifically a residue of alanine, isoleucine, leucine or valine.
  • DMT and CEPA of Formula 3 react to form a phosphodiester bond.
  • the DMT protecting group is released to form a hydroxyl group (-OH), and CEPA may react with the hydroxyl group, undergo oxidation, and then deprotection again to form an ester bond.
  • An example of a process for obtaining Chemical Formula 3 is as follows. Coupling a threonine derived structure, a polar amino acid derived structure or a hydrophobic amino acid derived structure to a base of a nucleotide can be performed, for example, by replacing a leaving group bound to the base of the nucleotide with a threonine derived structure, a polar amino acid derived structure or a hydrophobic amino acid derived structure. Can be.
  • the process of combining the threonine derived structure, the polar amino acid derived structure or the hydrophobic amino acid derived structure to the base of the nucleotide may further include replacing the sugar OH group of the nucleotide with O-CEPA, as shown in Scheme 2 below.
  • X is OH or H
  • B is adenine, thymine, guanine, cytosine or uracil
  • R is a threonine derived structure, a polar amino acid derived structure or a hydrophobic amino acid derived structure
  • DMT is 4,4'-dimethoxytrityl
  • CEPA is 2-cyanoethyl-N, N-diisopropylphosphoramidite
  • L represents a leaving group.
  • L may be, for example, halogen.
  • the polar amino acid derived structure is specifically a residue of serine, asparagine or glutamine
  • the hydrophobic amino acid derived structure is specifically a residue of alanine, isoleucine, leucine or valine.
  • Figure 2 shows an example of binding a threonine derived structure to the base of the nucleotide.
  • the base of the nucleotide shown in FIG. 2 is uracil and the sugar is deoxyribose.
  • Uracil contains an iodo (I) leaving group, which may be substituted with BnThr, a threonine derived structure.
  • I iodo
  • Scheme 2 Chemical Formula 3 may be obtained by substituting OH group of deoxyribose with O-CEPA.
  • Nucleotides of Formula 3, including modified bases can be combined with additional nucleotides by chemical methods using an nucleotide synthesizer.
  • An example of a precursor of a nucleotide including a modified base for binding the plurality of nucleotides by an enzymatic method is represented by the following Chemical Formula 4.
  • X is OH or H
  • B is adenine, thymine, guanine, cytosine or uracil
  • R is a threonine derived structure, a polar amino acid derived structure or a hydrophobic amino acid derived structure.
  • the polar amino acid-derived structure is specifically a residue of serine, asparagine or glutamine
  • the hydrophobic amino acid-derived structure is specifically a residue of alanine, isoleucine, leucine or valine.
  • Formula 4 including a modified base for binding the plurality of nucleotides by an enzymatic method may have a triphosphate.
  • Formula 4 may form a phosphodiester bond by the polymerase.
  • two phosphate groups are released from the triphosphate group represented by Chemical Formula 4.
  • FIG. 3 shows an example of a nucleotide comprising a base having a threonine derived structure for application to an enzymatic binding method.
  • Figure 3 (A) shows the deoxyadenosine triphosphate (dATP) with triphosphate, (B) shows the deoxyuridine triphosphate (dUTP).
  • dATP deoxyadenosine triphosphate
  • dUTP deoxyuridine triphosphate
  • a nucleic acid construct may be prepared by combining a nucleotide having a threonine-derived structure, a polar amino acid-derived structure, and a hydrophobic amino acid-derived structure to a base of the nucleotide with an additional nucleotide.
  • at least one base includes a threonine-derived structure, a polar amino acid-derived structure, or a hydrophobic amino acid-derived structure, regardless of whether it is bound by chemical or enzymatic methods.
  • the nucleotide to be further bound may or may not have a threonine derived structure, a polar amino acid derived structure or a hydrophobic amino acid derived structure to the base.
  • nucleic acid construct comprising a base having a threonine derived structure or a base having a polar amino acid derived structure and a base having a hydrophobic amino acid derived structure, a base having the threonine derived structure, a polar amino acid derived structure Synthesizing oligonucleotide or polynucleotide with a nucleotide comprising a base having or a base having a structure derived from the hydrophobic amino acid.
  • a nucleotide including a base having a threonine derived structure, a polar amino acid derived structure, or a hydrophobic amino acid derived structure and a nucleotide having no modified base may be mixed and combined.
  • the binding method may also be a chemical method or an enzymatic method.
  • an oligonucleotide bound through an oligo synthesizer may be a mixture of nucleotides including a modified base having a threonine derived structure and a nucleotide including a base not having a threonine derived structure.
  • FIG. 2 shows an example of a nucleotide comprising a base having a threonine derived structure for application to a chemical binding method
  • FIG. 3 shows one example of a nucleotide comprising a base having a threonine derived structure for application to an enzymatic binding method.
  • the phosphate group of the nucleotide may be triphosphate.
  • Figure 3 (A) shows the deoxyadenosine triphosphate (dATP) with triphosphate, (B) shows the deoxyuridine triphosphate (dUTP).
  • the nucleic acid construct can be obtained by synthesizing a nucleotide comprising a base having a threonine-derived structure. Or a nucleotide comprising a base having a polar amino acid derived structure and a nucleotide comprising a base having a hydrophobic amino acid derived structure. Therefore, the production process is simpler and more accurate than the introduction of the threonine-derived structure, the polar amino acid-derived structure, or the hydrophobic amino acid-derived structure after the nucleic acid structure assembly.
  • nucleic acid construct is prepared using a nucleotide comprising a base having a threonine derived structure, a polar amino acid derived structure, or a hydrophobic amino acid derived structure, a threonine derived structure, a polar amino acid derived structure, or the like directly to the base of the nucleotide constituting the double helix Hydrophobic amino acid derived structures are introduced.
  • a nucleic acid construct is prepared using a nucleotide comprising a base having a threonine derived structure, a polar amino acid derived structure, or a hydrophobic amino acid derived structure, a threonine derived structure, a polar amino acid derived structure, or the like directly to the base of the nucleotide constituting the double helix Hydrophobic amino acid derived structures are introduced.
  • the nucleic acid construct of the present invention has a high resolution by solving such a problem.
  • the minimum spacing between the two threonine derived structures may be 0.34 nm.
  • the minimum spacing of the two threonine-derived structures may be 2.3 nm.
  • a nucleotide sequence may be designed to arrange a base having a threonine derived structure, a base having a polar amino acid derived structure, or a base having a hydrophobic amino acid derived structure at a desired position.
  • the base having the polar amino acid-derived structure and the base having the hydrophobic amino acid-derived structure may be prepared to be located within 3 bp.
  • the polar amino acid-derived structure and the hydrophobic amino acid-derived structure may be prepared to be located within 3 bp.
  • the nucleic acid construct according to the present invention comprises a threonine derived structure; Including a polar amino acid-derived structure and a hydrophobic amino acid-derived structure, it can have the effect of suppressing the formation or growth of ice crystals, and can also suppress the recrystallization of ice.
  • the nucleic acid construct may have a plurality of threonine-derived structures on one surface, or a polar amino acid-derived structure and a hydrophobic amino acid-derived structure, and the number of modified bases per nucleic acid structure may be arbitrarily controlled. This can be adjusted according to the area or volume of the structure.
  • the position, number, and spacing of the threonine-derived structure, the polar amino acid-derived structure, or the hydrophobic amino acid-derived structure in the nucleic acid construct are not limited as long as they have an effect of interacting with ice to inhibit the formation or growth of ice crystals.
  • the base having a threonine derived structure, a base having a polar amino acid derived structure or a base having a hydrophobic amino acid derived structure may be located on one side of the nucleic acid structure.
  • One side of the nucleic acid construct may have a structure that is easy to interact with ice by increasing the density of a threonine-derived structure or a polar amino acid-derived structure and a hydrophobic amino acid-derived structure. More specifically, as illustrated in FIG. 8, it may be in a portion protruding to the outer side (for example, within 3 bp of the highest point protruding to the spiral outer side), but is not limited thereto.
  • FIG. 4 shows a nucleic acid construct comprising a base having a threonine derived structure that interacts with ice.
  • the nucleic acid construct may be in a form capable of locating a large amount of threonine derived structure, polar amino acid derived structure or hydrophobic amino acid derived structure on one side thereof.
  • the form of the nucleic acid construct is not particularly limited as long as it provides a nucleic acid construct having a large amount of threonine derived structure, polar amino acid derived structure or hydrophobic amino acid derived structure on one side.
  • the nucleic acid construct may be arranged such that at least one nucleic acid double strand comprises a plurality of first portions arranged in one direction.
  • 5 and 6 are perspective views showing one example of the nucleic acid construct of the present invention.
  • the nucleic acid constructs 100, 200 may comprise a first portion 101a, 101b, 101c and 101d; 201a, 201b, 201c, 201d, 201e and 201f and a second portion 102a, 102b, 102c. And 102d; 202a, 202b, 202c, 202d, 202e, and 202f.
  • the first portion and the second portion may be nucleic acid double strands in which two nucleic acid single strands are complementarily joined, or may be nucleic acid single strands. Or partially nucleic acid double stranded, and may be nucleic acid single stranded.
  • the nucleic acid construct may comprise a plurality of first portions, preferably four or six. 5 and 6, the plurality of first portions may be arranged in one direction.
  • the second part is to connect two first parts arranged in the one direction, it may be to connect the end and the end of each first part.
  • the second portion may be to connect the end and the end of each first portion in the shortest distance.
  • the second portion may not be arranged in one direction.
  • another end and end of each first part may not be connected to another second part.
  • another ends of the first portions 101a and 101b may not be connected to each other by another second portion. Can be.
  • the nucleic acid construct may be arranged such that at least one nucleic acid double strand comprises four first portions arranged in one direction.
  • the four first portions may be arranged such that a virtual line connecting the longitudinal section forms a quadrangle.
  • 7 is a cross-sectional view showing an example of the nucleic acid construct of the present invention.
  • Fig. 7A is a longitudinal section of the nucleic acid construct, and the four first portions constituting the nucleic acid construct form a quadrangular imaginary line connecting the longitudinal section.
  • the virtual line may be a line connecting a central portion of the first portion.
  • the nucleic acid construct may be arranged such that at least one nucleic acid double strand comprises six first portions arranged in one direction.
  • the six first portions may be arranged such that a virtual line connecting the longitudinal section forms a hexagon.
  • FIG. 7B is a longitudinal section of the nucleic acid construct, wherein the six first portions constituting the nucleic acid construct form a hexagonal imaginary line connecting the longitudinal section.
  • the virtual line may be a line connecting a central portion of the first portion.
  • the threonine-derived structure may be bound to a nucleotide at a high position (for example, within 3 bp of the highest point protruding to the lateral lateral surface) from the central axis of the nucleic acid double strand.
  • 8 shows a nucleic acid double strand comprising a base having a threonine derived structure.
  • the threonine-derived structure (Thr) may bind to a nucleotide at a high position from the center of the nucleic acid double strand, thereby increasing the probability of interacting with ice crystals.
  • Nucleotides at a higher position from the central axis of the nucleic acid double strand appear each time the nucleic acid double strand is turned once.
  • One cycle of DNA double helix rotation is 10.5 bp and the distance is 3.4 nm.
  • the threonine derived structure in the nucleic acid construct may be located at least every 10.5 bp.
  • the cycle in which the DNA double helix rotates once may vary depending on the shape and arrangement of the nucleic acid construct.
  • the base having the polar amino acid derived structure and the base having the hydrophobic amino acid derived structure may be located within 3 bp, and either the polar amino acid derived structure or the hydrophobic amino acid derived structure is positioned high from the central axis of the nucleic acid double strand (E.g., within 3 bp of the highest point protruding to the helical lateral surface).
  • Polar or hydrophobic amino acid-derived structures can bind to nucleotides at higher positions from the center of the nucleic acid double strand, thereby increasing the probability of interacting with ice crystals.
  • Nucleotides at a higher position from the central axis of the nucleic acid double strand appear each time the nucleic acid double strand is turned once.
  • One cycle of DNA double helix rotation is 10.5 bp and the distance is 3.4 nm.
  • the polar amino acid-derived structure or the hydrophobic amino acid-derived structure in the nucleic acid structure may be located at every 10.5 bp (10-11 bp).
  • the cycle in which the DNA double helix rotates once may vary depending on the shape and arrangement of the nucleic acid construct.
  • the present invention provides a composition for inhibiting ice crystal formation, growth or recrystallization comprising the nucleic acid construct of the present invention.
  • the nucleic acid construct according to the present invention comprises a threonine derived structure; Including a polar amino acid-derived structure and a hydrophobic amino acid-derived structure, it can have the effect of suppressing the formation or growth of ice crystals, and can also suppress the recrystallization of ice.
  • the composition may further include a stabilizer, an emulsifier, a surfactant, a solvent, and the like.
  • the additives contained in the composition are preferably sterile. These compounds can play a role of inhibiting nucleic acid degradation, inhibiting corruption, inhibiting oxidation, inhibiting microbial growth, emulsion stabilization, and the like.
  • the nucleic acid construct of the present invention may further comprise a cryopreservative, the cryopreservative may include all chemicals, biologically derived materials without limitation.
  • the composition may be a dried composition, and the dried composition may be in lyophilized form.
  • the composition can be used in a variety of fields where disorders occur due to ice crystallization of water.
  • it can be used in food field, machinery field, civil engineering field, cosmetic field, medical field using biomaterials and the like.
  • the food field by suppressing the ice crystallization of water contained in the food, it is possible to prevent changes in the taste or texture of the food.
  • improvements are possible.
  • machinery and civil engineering it can be used as an anti-freezing agent for moving parts, roads, and ground of machines.
  • the cosmetic field it can be used as an additive to prevent deterioration of quality of cosmetics.
  • a cosmetic containing an oil-fat component when frozen, the water contained in the cosmetic crystallizes, physically presses the oil-fat component, destroys its structure, and degrades quality and usability.
  • the composition according to the present invention when used, the structure of the oil-fat component is supported by preventing the ice crystallization of water, so that deterioration of the quality can be suppressed.
  • it can be used as a protective agent for cryopreservation of biological samples.
  • cryopreservation may cause damage to the biological sample by ice crystals that freeze and cause ice crystals to freeze.
  • the addition of the composition according to the present invention can suppress the generation or growth of ice crystals, thereby protecting biological samples from damage caused by ice crystals.
  • the present invention provides a biological sample preservative comprising the nucleic acid construct of the present invention.
  • the "biological sample” may be, but is not limited to, bacterial cells, yeast cells, plant cells, animal cells, insect cells, reptile cells, fish cells, mammalian cells, subcellular samples and cell extracts.
  • the biological sample may be a mammalian cell, a wide range of types of cells such as oocytes, embryos, leukocytes, erythrocytes, platelets, pancreatic islets and hepatocytes; Skin tissue, bone marrow tissue, corneal tissue and other broad types of tissue; And various types of organs such as liver, kidney, heart, brain, lung, pancreas, spleen, ovary, and stomach; but are not limited thereto.
  • types of cells such as oocytes, embryos, leukocytes, erythrocytes, platelets, pancreatic islets and hepatocytes
  • Skin tissue bone marrow tissue, corneal tissue and other broad types of tissue
  • organs such as liver, kidney, heart, brain, lung, pancreas, spleen, ovary, and stomach; but are not limited thereto.
  • microorganisms such as bacteria, soft tissues such as animals, plants, insects, etc. may exhibit less damage when frozen or thawed in the presence of a biological sample preservative of the present invention
  • Addition may be useful in situations where cell integrity is important or desirable (eg, tissue culture deposits) upon thawing before and after freezing. In other words, it is possible to minimize the loss of inherent properties or intrinsic form due to the freeze-thaw process.
  • biological sample preservatives comprising nucleic acid constructs can inhibit the growth of ice crystals, thereby greatly improving the survival rate during freezing and thawing of biological samples (eg, cells). Can be.
  • the biological sample preservative of the present invention may be in various forms such as solid, semisolid, fluid, gas, and the like.
  • it may be a fluid, but is not limited thereto.
  • the biological sample preservative of the present invention may further contain any of a broad mixture of salts, sugars, ions and other nutrients contained in an electrolyte solution known to be useful for preserving biological agents. These include tissue culture medium, organ perfusate and the like.
  • the nucleic acid construct of the present invention can be used as a protective agent in cryopreservation or cryopreservation of biological samples. Enzyme and heat treatment methods can be used to remove frozen material after biological sample storage.
  • the present invention provides a food comprising the nucleic acid construct of the present invention.
  • Water recrystallization in food deteriorates the taste and texture of the food.
  • Foods include, but are not limited to, ice cream, frozen yogurt, soups, puddings, sherbets, ice cream bars, frozen desserts such as custards, puddings, and other liquids or semi-liquids that are frozen.
  • Frozen vegetables such as celery, potatoes, asparagus, peas, carrots, beans, broccoli, sugar corn, spinach, kidney beans, and the like, and frozen meat such as pork and beef are also included in the present invention.
  • the food may be low fat spread, mayonnaise, yogurt, bakery, margarine, reconstituted fruit, jam, fruit preparation, fruit cow, ripple, fruit sauce, fruit stew, coffee bleach, instant fruit dessert, sweets (e.g. marshmallows) ), Potato-based foods (e.g. chips, french fries and croquettes), processed foods (e.g. casseroles and stews) and fine foods (e.g. dressings including salad dressings; ketchup, vinaigrette dressings and soups) ), But are not limited thereto.
  • sweets e.g. marshmallows
  • Potato-based foods e.g. chips, french fries and croquettes
  • processed foods e.g. casseroles and stews
  • fine foods e.g. dressings including salad dressings; ketchup, vinaigrette dressings and soups
  • the food may be a raw, processed or pasteurized food [raw or cooked meat, poultry, including beverages, raw meat, cooked meat, raw poultry products, cooked poultry products, raw seafood products, cooked seafood products. And seafood products], sausages, frankfurters, ready-to-eat foods, pasta sauces, pasteurized soups, marinades, oil-in-water emulsions, water-in-oil emulsions, cheese spreads, processed cheeses, dairy desserts, flavored milk, cream Fermented dairy products, cheese, butter, condensed milk products, cheese spreads, pasteurized liquid eggs, ice cream mixes, soy products, pasteurized liquid eggs, sugar products, fruit products, and fat-based or water-containing cows It may be a filled food, but is not limited thereto.
  • the food may be a confectionary product such as bread, cake, fine bakery and dough, but is not limited thereto.
  • the food of the present invention may be in a form in which the nucleic acid construct is incorporated in the entire food and / or a form applied to the surface of the food product, but is not limited thereto.
  • the food of the present invention may be prepared in various forms such as tablets, capsules, powders, granules, liquids, pills, powders, flakes, pastes, syrups, gels, jelly, bars, and the like, as well as processed foods. It can also be produced.
  • the food of the present invention may further include ingredients that are commonly added in the manufacture of food within the scope of the present invention, for example, may further include proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents.
  • Such carbohydrates are monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And polysaccharides such as, but are not limited to, conventional sugars such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • the flavoring agent may further include natural flavoring agents such as taumartin, stevia extract (for example, Rebaudioside A, glycyrgin, etc.) and synthetic flavoring agents such as saccharin and aspartame, but are not limited thereto. .
  • natural flavoring agents such as taumartin, stevia extract (for example, Rebaudioside A, glycyrgin, etc.) and synthetic flavoring agents such as saccharin and aspartame, but are not limited thereto. .
  • the food of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, And a carbonation agent used for the carbonated beverage.
  • the food of the present invention may contain a flesh for preparing natural fruit juice, fruit juice beverage and vegetable beverage.
  • These components can be used independently or in combination.
  • the proportion of such additives is not critical, but may be added in the range of 0.01 to 0.20 parts by weight per 100 parts by weight of the food composition of the present invention.
  • the mixed amount of the active ingredient can be suitably determined according to the purpose of use (prevention, health treatment). In general, in the manufacture of foods or beverages, it can be added in an amount of 0.0001 to 30% by weight, preferably 0.0001 to 10% by weight, more preferably 0.1 to 5% by weight relative to the total weight of the raw material. However, in the case of prolonged ingestion for health and hygiene purposes or for health control purposes, the amount may be adjusted below the above range.
  • the food of the present invention may further comprise a stabilizer.
  • Stabilizers include polypeptides such as gelatin; Plant extracts such as gum arabic, gatti gum, karaya gum, tragacanth gum; Seed gums such as locust bean gum, guar gum, tara gum, picillium seed gum, quince seed gum or tamarind seed gum; Konjac met; Seaweed extracts such as agar, alganate, carrageenan or purselane; Pectin, for example lower methoxyl or higher methoxyl-type pectin; Cellulose derivatives such as sodium carboxymethyl cellulose, microcrystalline cellulose, methyl and methylethyl cellulose, or hydroxylpropyl and hydroxypropylmethyl cellulose; And microbial gums such as dextran, xanthan or ⁇ -1,3-glucan; And the like, but is not limited thereto.
  • the food of the present invention is a sugar such as sucrose, fructose, dextrose, lactose, corn syrup, sugar alcohol; Or other raw materials such as pigments and flavorings.
  • the present invention also provides a cosmetic composition or a dermatological preparation comprising the nucleic acid construct of the present invention.
  • the optimum temperature of the cellular enzymes is lost due to a pronounced climate- and weather-induced temperature drop resulting in changes in cellular physiology in the cell and extracellular space, resulting in damage Can prevent or improve skin structure and cell damage caused by cold
  • the skin structure and cell damage is caused by cold, wind and / or UV light induced skin damage, skin erythema and skin pulling feeling and increased sensory sensitivity, temperature-sensitive skin, environment It includes, but is not limited to, changes in skin, lips and nose and oral mucosa and skin appendages due to stress (due to temperature changes and UV light, smoking, smog, reactive oxygen species, free radicals).
  • compositions, cosmetic compositions and topical dermatological preparations of the present invention may further comprise at least one of stabilizers, emulsifiers, surfactants and other additives known to those skilled in the art.
  • additives include, but are not limited to, anti-corruption agents, antioxidants, discoloration inhibitors, antimicrobial agents, emulsion stabilizers, and the like.

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Abstract

La présente invention concerne une structure d'acide nucléique dans laquelle au moins une base a une structure dérivée de la thréonine, ou au moins une base a une structure dérivée d'un acide aminé polaire choisi dans le groupe constitué par la sérine, l'asparagine et la glutamine, et au moins une base a une structure dérivée d'un acide aminé hydrophobe choisi dans le groupe constitué par l'alanine, l'isoleucine, la leucine et la valine.
PCT/KR2017/003274 2017-03-27 2017-03-27 Structure fonctionnelle d'acide nucléique et son procédé de préparation Ceased WO2018182054A1 (fr)

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