WO2012149906A1 - Modified nucleic acid structure having anti-hiv-1 fusion activity - Google Patents

Abstract

The present application relates to a modified nucleic acid structure, as represented in general formula (I), and pharmaceutically acceptable salts or solvates thereof, the higher order structures of double helix, triple helix, and quadruple helix of the nucleic acid structure, the preparation method therefor, and the use thereof in preparing medications against viruses. R¹-R⁴，m₁，m₂，X，Y, and B¹-B⁵ are as defined in the description.

Description

 Modified nucleic acid structure having anti-H I V-1 fusion activity

 The present invention relates to a modified nucleic acid structure, or a pharmaceutically acceptable salt or solvate thereof, a double helix, a triple helix and a four helix high-order structure of the nucleic acid structure, a process for the preparation thereof, and use thereof for preparing an antiviral drug . Background of the invention

 The development of nucleic acid drugs for anti-tumor, anti-viral and cardiovascular disease treatments has been a hot topic in recent years, including antisense nucleic acids, ribozymes, small interfering RM (s iRNA) and adaptors. The first three are gene therapy drugs designed for the expression of disease-causing genes or regulatory related sequences, while the aptamer-type nucleic acids specifically bind to specific target proteins with their unique high-level structures to achieve the function of inhibiting target proteins. purpose.

 In cells, nucleic acids exist in a variety of high-order structural types. In addition to the ubiquitous DM duplex structure, unknown RNA or high-stranded structures of DNA single strands may be involved in many life processes of cells, playing various known and Unknown feature. For example, the four-helix structure formed by the G-rich fragment has important biological significance. The well-known telomere structure contains a highly repetitive G-rich sequence, (GGGTTA) n, which is closely related to cell life. G-rich fragments, such as the c-myc promoter, immunoglobulin transformation region, insulin regulatory sequences, etc., have also been found in other gene sequences, and are involved in the regulation of multiple functions. It is known that there are 375,000 potential G-tetra-helix structures in cells, and the specific life processes involved in them have yet to be further studied.

The G-tetra-helical structure is a very unique class of high-order structures formed by four stretches of nucleotide fragments containing contiguous G, which can be derived from within or between chains. The four bases G on the four fragments (chains) can form a quadruplex plane by hydrogen bonding, and such planes are continuously stacked to form a four-helix structure, and cations such as Na+ and yttrium are used for this. The structure provides further stability and they create electrostatic interactions with the renegade of the guanine. The overall conformation of the four helix is in a variety of forms, depending on factors such as the type of cation, the length of the attached ring, the terminal group (introduced or the base itself). Under the condition of physiological salt concentration, the four-helical structure has a melting temperature above 60 and can exist stably under physiological conditions. This may also be the structural basis for biological evolution to select its biological function.

The biologically functional non-biological G-tetra-helical structure was originally selected from a library of nucleic acid sequences and functions by specifically binding to a specific protein, such as an aptamer that specifically binds to thrombin. It has also been found by combinatorial chemistry that a plurality of G-tetra-helix-containing structures have an activity of inhibiting HIV-1. 0jwang et al. reported a 17-mer G-tetra-helical structure with activity to inhibit HIV-1 integrase. Wyatt et al. used a combinatorial chemistry method to screen another G-tetra-helix structure with anti-HIV activity, 5320: 5 ^, -d (TTGGGGTT) -3 ^/ , which forms a stable intermolecular four-helix structure in the presence of ruthenium. Infection of HIV-1 from cells to cells and from viruses to cells is inhibited by binding to the V3 loop of the HIV viral surface protein gpl20. 5'-d (TGGGAG) -3' is simplified from a 15mer G-tetra-helix structure, introducing a large fat-soluble group on the 5'-hydroxyl group of its 5'-end sugar ring. The fat-soluble group together with the four helix confers activity to the structure to inhibit HIV fusion.

 At present, a variety of small molecule drugs and peptide drugs have been used for HIV-1 treatment, which has played a huge role in controlling the harm of AIDS. Unfortunately, these drugs have different degrees of drug resistance during the treatment. Therefore, the development of new structures and mechanisms for anti-HIV-1 drugs is still a hot research direction for medicinal chemistry against HIV-1 infection.

The present invention is based on the structural requirements of the action of the nucleic acid four-helix anti-HIV-1, that is, the polyanion of the nucleic acid backbone and the fat-soluble group of a certain volume of the nucleic acid structure end, propose a new modification strategy, through chemical modification and a new skeleton design. Looking for activity A new structure that is higher and more suitable as a drug, as one of the effective ways to screen anti-HIV-1 drugs. Introducing various fat-soluble group modifications at the base of the 5'-nucleoside monomer, and/or combining with modifications on the 5'-ribose; developing a double helix, a triple helix, and a four helix backbone structure, A new structure that inhibits HIV-1 fusion activity as a new therapeutic candidate against HIV-1 infection. Summary of the invention

Summary of invention

 The present invention relates to a modified nucleic acid structure having anti-HIV-1 fusion activity, the sequence of which is as shown in the general formula (I):

(I)

R ^{1 is} attached at the 5'-end of the nucleotide sequence, independently selected from the nucleoside monomer structure of Formula 1-6, which is 3'-hydroxy or 5'-hydroxy with the nucleoside Acid sequence linkage;

R²连接在核苷酸序列的 y -端, 独立地选自： 氢原子， 甲基 磷酰基， 2-氯苯基磷酰基， 甲基硫代磷酰基， 甲基膦酰基， 甲基 硫代膦酰基， 苯基膦酰基， 2-羟乙基磷酰基， 2-羟乙基硫代磷酰 基， 苯基磷酰基， 4-氯苯基磷酰基， 2-羟基- 3-乙酰胺基-丙基；

R ^{2 is} attached at the y-terminus of the nucleotide sequence, independently selected from the group consisting of: hydrogen atom, methylphosphoryl group, 2-chlorophenylphosphoryl group, methylthiophosphoryl group, methylphosphono group, methylthio group Phosphono, phenylphosphono, 2-hydroxyethylphosphoryl, 2-hydroxyethylthiophosphoryl, phenylphosphoryl, 4-chlorophenylphosphoryl, 2-hydroxy-3-acetamido-propyl base;

R ³ is absent or is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogen atom, C 1-4 alkyl substituted by amino or C 1-4 alkoxy or halogen atom, substituted or not Substituted aryl and substituted or unsubstituted aralkyl;

X is selected from the group consisting of an oxygen atom, a sulfur atom, an NH ₂ , NH and a C1-6 alkylene chain; wherein when X is NH ₂ , R ³ is absent;

R ⁴ is absent or is selected from a hydrogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylamino group, a halogen atom, and a C1-substituted by an amino group or a C1-6 alkoxy group or a halogen atom. a 6 alkyl group, a substituted or unsubstituted aryl group and a substituted or unsubstituted aralkyl group;

Y is selected from the group consisting of an oxygen atom, a sulfur atom, NH ₂ , NH, a hydrogen atom, a fluorine atom and a C1-6 alkylene group, wherein when Y is H, NH ₂ or F, R ³ is absent;

13⁄4 and m ₂ represent the number of structural units containing bases B ⁴ and B ¹ -B ² -B ³ - B ⁵ , each independently being 1-15;

B ¹ , B ² , B ³ , B ⁴ and B ⁵ are bases on a nucleotide sequence, each independently selected from the group consisting of A, G, C, T, mC, mG and unnatural bases, and combinations thereof;

X ¹ is absent or is selected from a C1-6 alkylene group, a C2- 6 alkenylene group and a C2- 6 alkynylene group, wherein the C1-6 alkylene group, the C2- 6 alkenylene group and the C2- 6 group One or more methylene groups in the alkynylene group are optionally replaced by an oxygen atom, a sulfur atom, an amide group or an ester group;

X ² is absent or is selected from an oxygen atom, CH ₂ , NH and a sulfur atom;

X ^{3 is} selected from the group consisting of CH and a nitrogen atom;

 Z is selected from a carbon atom or a silicon atom;

R ⁵ , R ⁶ and R ^{7 are the} same or different and are each independently selected from C1-4 alkyl, fluorenyl, xanthenyl, unsubstituted or C6-20 aryl which is mono- or polysubstituted by R ⁸ , and Replace Or a thiol group which is mono- or polysubstituted by R ⁸ ;

R ⁸ is C1-4 alkyl, C1-4 haloalkyl, halogen atom, nitro, cyano, amino, C1-4 alkoxy, C1-4 alkylthio, substituted or unsubstituted aryl, aryloxy Alkyloxy group;

In the nucleoside monomer 1-3, R ⁵ , R ⁶ , R ⁷ and Z are bonded to S'-O or X ²

R ⁷

 R, |—

当核苷单体 1-3 中 5'位置不存在基团The groups _R ^{Z_ are the} same or different and may exist simultaneously or separately, at this time

When the nucleoside monomer 1-3 has no group at the 5' position

R ⁷

When R ^Z —, nucleoside monomers 1-3 are linked to the nucleotide sequence by a 5'-hydroxyl group. The present invention is based on the structural requirements of the four-helix structure fragment for inhibiting the entry activity of HIV-1, and proposes a novel terminal modification pathway for the four-helix structure.

 The present invention firstly proposes and demonstrates that the modified double helix and triple helix nucleic acid structures also have better activity for inhibiting HIV entry.

 The present invention relates to the introduction of various fat-soluble groups at a plurality of positions of terminal structural units; and the introduction of such modifications into nucleic acid sequences to form stable high-order structures under simulated physiological conditions, such as double helices, triple helices, and four The helical structure, which exhibits activity against HIV-1 entry, has potential research and development value as an anti-HIV-1 entry drug candidate.

 The novel structural nucleic acids involved in the present invention have significant structural differences from existing marketed small molecule or peptide anti-HIV drugs, and the new structure is advantageous for overcoming the resistance of existing anti-HIV drugs.

 The present invention provides a method of designing and synthesizing a modified monomer comprising introducing various fat-soluble groups into the base of the nucleoside monomer and ribose, and converting into a phosphoramidite monomer suitable for solid phase synthesis of the nucleic acid.

The present invention relates to a process for the preparation and purification of nucleic acid structural fragments containing modified monomers. The invention also relates to the assembly of various modifications on the high-level structure of nucleic acids, including

Various modifications in the base of the 5'-nucleoside monomer, modification on the 5'-ribose, and modification on the phosphodiester bond, revealed a novel structure that inhibits HIV-1 entry activity, as an anti-HIV -1 new therapeutic candidate for infection.

In the general formula (I), the sequence composition produced by B ¹ , B ² , B ³ , B ⁴ , B ⁵ contains one or more GGG or GGGG fragments, and a four-helix structure is formed; A purine or a perpyrimidine forms a triple helix structure; if it is a random combination of natural bases, a double helix structure is formed. Also, the complementary nucleic acid sequence in the triple helix and the double helix structure may be natural or may be a modified sequence as defined in the present invention.

 Non-natural bases include structures resulting from the modification of four bases such as A, G, C, T, etc., to improve the thermal stability, chemical stability and enzyme stability of the helical structure: for A and G Modification of the five-membered ring moiety, such as the base moiety in Formulas 2 and 3; introduction of a substituent at the 5-position of T, such as the base moiety of Formula 1, etc.; substituents may also include chlorine, bromine, iodine, etc. Halogen atom;

When nucleoside monomers 1-6 are used for nucleic acid structure modification, they are used in the synthesis of nucleic acid structures in the form of phosphoramidite monomers, which are used for solid phase synthesis of phosphorous amide monomer 7-12, respectively. ) , As follows. Accordingly, the present invention also provides phosphoramidite monomer structures 7-12 and methods for their synthesis.

N

N

 8 9

 10 1 1 12

 a phosphoramidite monomer structure for nucleic acid structure synthesis 7-12 wherein

In the phosphoramidite monomer 7-12, X ¹ , X ² , X ³ , Z, R ⁵ , R ⁶ , R ^{7 have} the same meanings as in the formula (I);

R ⁹ is a protecting group for the 6-position amino group of adenine and its analogs, including benzoyl, di-n-butylaminomethyl, dimethylaminomethyl, acetyl, propionyl, butyryl, formyl, Among them, a benzoyl group, a di-n-butylaminomethyl group, a dimethylaminomethyl group, an acetyl group;

R ¹ " is a 2-amino protecting group for guanine and its analogs, including isobutyryl, di-n-butylaminomethyl, dimethylaminomethyl, acetyl, propionyl, butanoyl, benzoyl , formyl, wherein, isobutyryl, di-n-butylaminomethyl, dimethylaminomethyl, acetyl is preferred.

 The present invention also relates to a nucleic acid structure represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.

The present invention relates to the nucleic acid structure represented by the formula (I), using other nucleic acid drugs (such as Transport strategy for s iRNA, antisense nucleic acids, aptamers, ribozymes, etc.: complexes formed with various cationic polymers such as cationic liposomes; ligands with PEG, cholesterol, target cell surface receptors, etc. Binding to improve the transport efficiency of such nucleic acid drugs.

 The invention further relates to a pharmaceutical composition comprising a nucleic acid structure of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. In one embodiment, the composition further includes other drugs that treat viral infections. In one embodiment, the virus is in particular an HIV-1 virus.

 The invention further relates to the use of a nucleic acid structure of the formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a viral infection. In one embodiment, the virus is an HIV-1 virus.

 The invention further relates to a method of treating a viral infection, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a nucleic acid structure of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the virus is an HIV-1 virus. DRAWINGS

 Figure 1 contains a CD spectrum of a four-helix nucleic acid structure of the general formula (I), which is a circular dichroic transmission map for determining the high-order structure of the nucleic acid of the general formula (I) of the present invention, wherein 01 to 07 respectively refer to LK- in Table 2; CW-01 to LK-CW-07. LK-CW-01 to LK-CW-07 both show the characteristic CD spectrum of the parallel four-helical structure.

 Figure 2 contains a CD spectrum of the double-stranded nucleic acid structure D01+D02 of the general formula (I), which is a circular dichroism chromatogram for determining the high-order structure of the nucleic acid of the general formula (I) of the present invention, wherein the structure D01+D02 shows a double helix structure Characteristic CD peak. Detailed description of the invention

All documents cited in the present invention, the entire contents of which are incorporated herein by reference. And if the meaning expressed by these documents is inconsistent with the present invention, the expression of the present invention shall prevail. Moreover, the various terms and phrases used in the present invention have the ordinary meanings well known to those skilled in the art, and even though the present invention is intended to provide a more detailed description and explanation of the terms and phrases herein, such terms and phrases are Inconsistent with the well-known meaning, the meaning expressed in the present invention shall prevail.

 The present invention utilizes nucleoside monomers 1-6 to structurally modify the nucleic acid sequence of formula (I) to obtain biological activity against viruses, particularly anti-HIV-1 viruses.

A first aspect of the invention relates to an oligonucleotide of the formula (I) or a pharmaceutically acceptable agent thereof

 (I)

 among them

R ^{1 is} attached at the 5'-end of the nucleotide sequence, independently selected from the nucleoside monomer structure of Formula 1-6, which is 3'-hydroxy or 5'-hydroxy with the nucleoside Acid sequence linkage;

R²连接在核苷酸序列的 y -端, 独立地选自： 氢原子， 甲基 磷酰基， 2-氯苯基磷酰基， 甲基硫代磷酰基， 甲基膦酰基， 甲基 硫代膦酰基， 苯基膦酰基， 2-羟乙基磷酰基， 2-羟乙基硫代磷酰 基， 苯基磷酰基， 4-氯苯基磷酰基和 2-羟基- 3-乙酰胺基-丙基； 优选氢原子， 甲基磷酰基， 2-氯苯基磷酰基， 甲基硫代磷酰基， 2 -羟乙基磷酰基或 2-羟基- 3-乙酰胺基-丙基；

R ^{2 is} attached at the y-terminus of the nucleotide sequence, independently selected from the group consisting of: hydrogen atom, methylphosphoryl group, 2-chlorophenylphosphoryl group, methylthiophosphoryl group, methylphosphono group, methylthio group Phosphono, phenylphosphono, 2-hydroxyethylphosphoryl, 2-hydroxyethylthiophosphoryl, phenylphosphoryl, 4-chlorophenylphosphoryl and 2-hydroxy-3-acetamido-propyl Preferred; a hydrogen atom, a methylphosphoryl group, a 2-chlorophenylphosphoryl group, a methylthiophosphoryl group, a 2-hydroxyethylphosphoryl group or a 2-hydroxy-3-acetamido-propyl group;

R ³ is absent or is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogen atom, C 1-4 alkyl substituted by amino or C 1-4 alkoxy or halogen atom, preferably A Base, ethyl, 2-aminoethyl, 2-methoxyethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, more preferably methyl, ethyl, 2-aminomethyl, 2-methoxyethyl or propyl; or R ³ is a substituted or unsubstituted aryl group, wherein aryl means 6-20 carbon atoms, preferably 6-16 carbon atoms, More preferably, an aromatic ring structure of 6 to 10 carbon atoms, the aryl group having no substituent or having at least one substituent; including a phenyl group, a C1-4 alkylphenyl group (e.g., 2-methylphenyl group, or 3-B Phenylphenyl), halophenyl (such as 2-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl or 2-iodophenyl), nitrophenyl (such as 2- Nitrophenyl or 4-nitrophenyl), C1-4 alkoxyphenyl (such as 4-methoxyphenyl, or 4-ethoxyphenyl), C1-4 alkylthiophenyl ( Such as 4-methylthiophenyl, or 4-ethylthiophenyl), naphthyl, phenanthryl, anthracenyl and fluorenyl, among them, An unsubstituted phenyl group, a methoxyphenyl group, a halogenated phenyl group, and a nitrophenyl group; or R ³ is a substituted or unsubstituted aralkyl group, wherein the aralkyl group has 1 to 4 carbon atoms An alkyl group substituted with at least one (1-3, preferably one) of the above aryl groups, including benzyl, methylbenzyl, ethylbenzyl, methoxybenzyl, ethoxybenzyl, fluoro Benzyl, chlorobenzyl, bromobenzyl, chloronaphthylmethyl, fluorenylmethyl, phenanthromethyl, fluorenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenylethyl, 2-Phenylethyl, 2,2-diphenylethyl, 2, 2, 2-triphenylethyl, 3, 3, 3-triphenylpropyl, 1-naphthylethyl, 2-naphthylethyl Base, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-calylpropyl; X is selected from the group consisting of oxygen atoms, sulfur atoms, NH ₂ , NH and C1-6 alkylene chains, such as methylene, ethylene, propylene, butylene, pentylene; wherein when X is NH ₂ , R ³ is absent; preferably an oxygen atom, a sulfur atom or a methylene group;

R ⁴ is absent or is selected from a hydrogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylamino group, a halogen atom, and a C1-substituted by an amino group or a C1-6 alkoxy group or a halogen atom. 6 alkyl, preferably methyl, ethyl, 2-aminoethyl, methoxymethylene, 2-methoxyethylidene, 3-methoxypropylene, 2-ethoxymethylene , 2-ethoxyethylene, 2-propoxyethylene, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, more preferably methyl, ethyl, 2-aminoethyl, 2-methoxyethyl, methoxymethylene, 2-ethoxymethylene or propyl; or R ⁴ is a substituted or unsubstituted aryl group, wherein aryl means An aromatic ring structure having 6 to 20 carbon atoms, preferably 6 to 16 carbon atoms, more preferably 6 to 10 carbon atoms, the aryl group having no substituent or having at least one substituent including a phenyl group, a C1-4 alkane Phenylphenyl (such as 2-methylphenyl, or 3-ethylphenyl), halophenyl (such as 2-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl) Or 2-iodophenyl), nitrophenyl (such as 2-nitrophenyl or 4-nitrophenyl), C1-4 alkoxy Phenylphenyl (such as 4-methoxyphenyl, or 4-ethoxyphenyl), C1-4 alkylthiophenyl (such as 4-methylthiophenyl, or 4-ethylthiophenyl) , naphthyl, phenanthryl, fluorenyl and fluorenyl, wherein, preferably, unsubstituted phenyl, methoxyphenyl, halophenyl, and nitrophenyl; or R ⁴ is substituted or unsubstituted aralkyl a arylalkyl group, which is an alkyl group having 1 to 4 carbon atoms, which is substituted with at least one (1-3, preferably 1) of the above aryl groups, including benzyl, methylbenzyl, ethylbenzyl , methoxybenzyl, ethoxybenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, chloronaphthylmethyl, fluorenylmethyl, phenanthrenyl, fluorenylmethyl, diphenyl Methyl, triphenylmethyl, 1-phenylethyl, 2-phenylethyl, 1, 1-diphenylethyl, 2, 2, 2-triphenylethyl, 3, 3, 3-three Phenylpropyl; 1-naphthylethyl, wherein benzyl and phenethyl are preferred;

Y is selected from the group consisting of an oxygen atom, a sulfur atom, NH ₂ , NH, a hydrogen atom, a fluorine atom and a C1-6 An alkylene group, such as a methylene group, an ethylene group, a propylene group, a tetramethylene group, or a pentamethylene group; wherein when Y is H, NH ₂ or F, R ³ is absent; a methylene group is preferred. a hydrogen atom or a fluorine atom;

13⁄4 and m ₂ represent the number of structural units containing the bases B ⁴ and B ¹ -B ² -B ³ - B ⁵ , each independently being 1-15, ii preferably 1-10, more preferably 1-6, most Preferably 1-4, even most preferably 1 or 2; m ₂ is preferably 1-10.

B ¹ , B ² , B ³ , B ⁴ and B ⁵ are bases on a nucleotide sequence, each independently selected from the group consisting of A, G, C, T, mC, mG and unnatural bases, and combinations thereof;

X ¹ is absent or is selected from a C1-6 alkylene group such as a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group, wherein a methylene group, an ethylene group, a propylene group is preferred. C2-6 alkenylene group, such as (E)-vinyl group, (Z)-vinyl group, (E)-propenyl group, (Z)-propenyl group, (E)-butenyl group, (Z) butene (E)-pentenyl, (Z)-pentenyl, (E)-hexenyl, (Z)-hexenyl, wherein (E)-propenyl, (Z)-propenyl And a C2-6 alkynylene group, such as propynyl, butynyl, pentynyl, hexynyl, wherein a propynyl or butynyl group is preferred; wherein the C1-6 alkylene group, C2-4 One or more methylene groups in the alkenyl group and the C 2 - 6 alkynylene group are optionally replaced by an oxygen atom, a sulfur atom, an amide group or an ester group;

X ² is absent or is selected from an oxygen atom, CH ₂ , NH and a sulfur atom;

Or preferably X ¹ and X ² may together form a methyleneoxy group, an ethyleneoxy group, a propyleneoxy group, a 1-propynyloxy group, a 3-propyleneoxy group or a 1-propenyloxy group;

X ^{3 is} selected from the group consisting of CH and a nitrogen atom;

 Z is selected from a carbon atom or a silicon atom;

R ⁵ , R ⁶ and R ^{7 are the} same or different and are each independently selected from C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl a group, wherein a tert-butyl group is preferred; and a C6-20 aryl group which is unsubstituted or monosubstituted or polysubstituted by R ⁸ , preferably a C 6-16 aryl group, further preferably a C 6-10 aryl group; the aryl group has no substituent or There are at least one substituent; an unsubstituted aryl group such as phenyl, 1-naphthyl, 2-naphthyl, 4-phenanthryl, 9-fluorenyl, 2-indenyl, fluorenyl, wherein the preferred aryl group is a phenyl group and a naphthyl group, more preferably a phenyl group; the aryl group has 1 to 5 substituents R ⁸ , preferably 1 to 3, more preferably 1 or 2;

R ⁸ is as defined below: C1-4 alkyl, C1-4 haloalkyl, halogen atom, nitro, aryl, amino, C1-4 alkoxy, C1-4 alkylthio, aryl, aryloxy, aryl An alkyl group or an aralkyloxy group; wherein the aryl group means an aromatic ring structure having 6 to 20 carbon atoms; the aralkyl group is an alkyl group having 1 to 4 carbon atoms, which is substituted with at least one of the above aryl groups; Aryloxy means aryl-0-, wherein aryl is as defined above; aralkyloxy means aralkyl-0-, wherein aralkyl is as defined above;

An example of the definition of R ⁸ is as follows:

 C1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, preferably methyl and tert-butyl;

 C1-4 haloalkyl: fluoromethyl, trifluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 2, 2, 2-trichloroethyl, 2-fluoroethyl, 2 -chloroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, etc., preferably trifluoromethyl and 2, 2, 2-trichloroethyl;

 Halogen atom: such as fluorine, chlorine, bromine, iodine atom, preferably fluorine and chlorine atom; nitro group, cyano group and amino group;

 C1-4 alkoxy: such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy, preferably methoxy and Tert-butoxy;

 C1-4 alkylthio: methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, and tert-butylthio, preferably methylthio and tert-butyl Butylthio; aryl: such as phenyl or naphthyl;

 Aryloxy: such as phenoxy or naphthyloxy;

 Aralkyl group: such as benzyl or phenethyl;

Aralkyloxy: such as benzyloxy or phenethyloxy; Or R ⁵ , R ⁶ and R ^{7 are the} same or different and are each independently selected from the group consisting of fluorenyl, unsubstituted or substituted, and the substituent is the same as R ⁸ ; the number of substituents is 1-5, preferably 1-3 Further, preferably one; such as 9, 10-蒽醌- 1-, 9, 10-蒽醌- 2-, 4-methyl- 9, 10-蒽醌- 1-, 5-methoxy- 9, 10-蒽醌- 1- , 7-chloro- 9, 10-蒽醌-1-, 8-fluoro- 9, 10-蒽醌- 2- , 6-ethyl- 9, 10-蒽醌- 2-, 8-ethoxy-, 9, 10-蒽醌- 2-, 9, 10-蒽醌- 1-, 6-hydroxy- 9, 10-蒽醌- 1-, wherein, preferably, unsubstituted anthracene醌基;

Or R ⁵ , R ⁶ and R ⁷ and Z are selected from the group consisting of fluorenyl, P ton, preferably 9-fluorenyl, 9-fluorene;

In the nucleoside monomer 1-3, R ⁵ , R ⁶ , R ⁷ and Z are bonded to S'-O or X ²

R ⁷

 R, |—

The groups _R ^{Z_ are the} same or different and may exist simultaneously or separately, at this time When the nucleoside monomer 1-3 has no group at the 5' position

R ⁷

When R ^Z —, nucleoside monomers 1-3 are linked to the nucleotide sequence by a 5'-hydroxyl group. In the general formula (I), the sequence composition produced by B ¹ , B ² , B ³ , B ⁴ , B ⁵ contains one or more GGG or GGGG fragments, forming a four-helix structure; A composition consisting of a full purine or a perpyrimidine forms a triple helix structure; if it is a random combination of natural bases, a double helix structure is formed. Furthermore, the complementary nucleic acid sequence in the triple helix and the double helix structure may be unmodified or may be a modified sequence as defined in the present invention.

Non-natural bases include structures resulting from the modification of four bases such as A, G, C, T, etc., to improve the thermal stability, chemical stability and enzyme stability of the helical structure: Modification of the five-membered ring moiety, such as the base moiety in Formulas 2 and 3; introduction of a substituent at the 5-position of T, such as the base moiety of Formula 1, etc.; The substituent on the modified base may further include a halogen atom such as chlorine, bromine or iodine; in the formula (I), B ¹ , B ² , B ³ , B ⁴ and B ⁵ contain three consecutive G groups, such as d (TGGGAG) ₄ , d (GGGTG) " d (TGGGA) ₄ , d (TGGGA) ₄ , d (TGGGA) ₄ , d (TGGGA ) ₄ , d (TGGGA ) ₄ , d (TGGGA ) _{4 ,} etc . A stable four-helical structure is formed in the presence of ions; when B ¹ to B ⁵ are randomly distributed base compositions, such as d (TCTGCATG) and d (CATGCAGA), a double helix structure is formed; in these two types of structures The modification strategy of the present invention is introduced, and the 5'-end is substituted with the modified monomer 1-6 to obtain an activity for inhibiting the entry of HIV-1. In one embodiment of the general formula (I) of the present invention, !^ and m ₂ is independently 1-10, preferably 1-6, more preferably 1-4. ii preferably 1-4, m ₂ preferably 1 to 10.

In one embodiment of the general formula (I) according to the invention, R ^{1 is} attached at the 5'-terminus, independently selected from the monomer structure 1-6; R ^{2 is} attached at the 3'-position, independently selected from: a hydrogen atom , methylphosphoryl, 2-chlorophenylphosphoryl, methylthiophosphoryl, 2-hydroxyethylphosphoryl and 2-hydroxy-3-acetamido-propyl.

In one embodiment of the formula (I) according to the invention, X ¹ is C1-6 alkylene, C1-6 alkenylene or C1-6 alkynylene, wherein one of said C1-6 alkylene groups Or a plurality of methylene groups are optionally replaced by oxygen atoms; X ² is an oxygen atom, CH ₂ , NH or a sulfur atom; X ¹ and X ^{2 together} form a methyleneoxy group, an ethyleneoxy group, a propyleneoxy group , i- 1-propynyloxy, or i- 1-propenyloxy; X ³ is CH or a nitrogen atom.

In one embodiment of the formula (I) according to the invention, X and R ^{3 together} form a 0H, SH, methoxy, ethoxy, propoxy or benzyloxy group.

In one embodiment of the invention of formula (I), Y is and R ⁴ - together form a hydroxyl group, a fluorine atom, a hydrogen atom, a methoxy group, ethoxy, propoxy, methoxymethylene, methoxy, methyl Oxyethyleneoxy, ethoxymethyleneoxy, methylamino or ethylamino. A second aspect of the invention relates to a phosphoramidite monomer 7-12 for the synthesis of formula (I) derived from monomers 1-6 and a process for its synthesis.

10 12 phosphoramidite monomers 7-12, X ¹ , X ² , X ³ , Z, R ⁵ , R ⁶ , R ^{7 have} the same definitions as in the formula (I);

R ⁹ is a protecting group for the 6-position amino group of adenine and its analogs, including benzoyl, di-n-butylaminomethyl, dimethylaminomethyl, acetyl, propionyl, butyryl, formyl, Among them, a benzoyl group, a di-n-butylaminomethyl group, a dimethylaminomethyl group, an acetyl group;

R ¹ " is a 2-amino protecting group for guanine and its analogs, including isobutyryl, di-n-butylaminomethyl, dimethylaminomethyl, acetyl, propionyl, butanoyl, benzoyl , formyl, wherein, isobutyryl, di-n-butylaminomethyl, dimethylaminomethyl, formyl, acetyl is preferred. A third aspect of the invention relates to the synthesis of nucleoside monomers 1-6, exemplified by a structure in which the 2'-position is substituted with a hydrogen atom.

The synthetic route of Compound 1 is shown in Reaction Scheme 4 and Reaction Scheme 5. When X ¹ is a methylene group, an ethylene group, a propylene group, and X ² is an oxygen atom, the synthetic route shown in Reaction Scheme 4 is employed. The hydroxyl group at the 5 and 5' positions of the compound la is reacted with a halide containing an aromatic group such as trityl chloride (Trt-Cl), 4,4'-dimethoxy-trityl chloride ( DMT-C1), tert-butyldiphenylchlorosilane (TBDPS-C1), which gives the important intermediate 1, 1 at the 5 and 5'-positions of the R ⁵ R ⁶ R ⁷ Z group; if R ⁵ R ⁶ R ⁷ Z group is different at the 5 and 5' positions, and the compound lb is used as a raw material, and the R ⁵ R ⁶ R ⁷ Z group has been introduced at the 5 position thereof, and the glycosidation reaction and the sugar ring are removed. The protecting group (Tol, p-methylbenzoyl) gives the important intermediate lc, which introduces the desired R ⁵ R ⁶ R ⁷ Z group at its 5'-position, giving the 5 and 5'-positions with different lipids. Monomer 1 of a soluble substituent. The nucleoside monomer 1 is further converted to a phosphoramidite monomer 7 for DNA solid phase synthesis.

 1c

Reaction Scheme 4 Synthesis route of compound 1 and its phosphoramidite monomer 7 When X ¹ is another group, X ² is oxygen or a carbon atom, starting with 5-iodooxyuridine a coupling reaction to introduce an olefinic bond or a block bond to the arm, and the two link arms can be hydrogenated to an alkylene linker, and then the desired group is introduced at the 5'-position, as in Scheme 5.

 1 b

Scheme 5 Synthesis of Compound 1 and Its Important Intermediate lb The synthetic route of Compound 2 and its phosphoramidite monomer 8 is shown in Reaction Scheme 6. Starting from compound 2a, the coupling reaction generally introduced into the 7-position substituent group R ⁵ R ⁶ R ⁷ Z group, X ¹ an alkenyl group, an alkynyl group is introduced, and may be alkenyl and alkynyl groups via hydrogenation reaction Conversion to an alkylene group gives the key intermediate 2b, introducing the same or different R3⁄4 ⁷ Z group at the 5' position of 2b to give compound 2, and introducing a protecting group R ⁹ such as a benzoyl group at the 6-amino group of 2 Acetyl, di-n-butylaminomethyl, or dimethylaminomethyl, gives the key intermediate 2c, which is further converted to its phosphoramidite monomer 8.

The synthetic route of Compound 3 and its phosphoramidite monomer 9 is shown in Reaction Scheme 7. Starting from compound 3a, a substituent R ⁵ R ⁶ R ⁷ Z group at the 7 position is generally introduced by a coupling reaction, X ¹ is an alkenyl group-containing group, and a hydrogen group can be hydrogenated to react an alkenyl group and Conversion of an alkynyl group to an alkylene group gives the key intermediate 3b, introducing the same or different R ⁵ R ⁶ R ⁷ Z group at the 5' position of 3b to give compound 3, and introducing a protecting group at the 2-amino group of 3, Such as isobutyryl, acetyl, di-n-butylaminomethyl, dimethylaminomethyl, formyl, gives the key intermediate 3c, which is further converted to its phosphoramidite monomer 9.

NCCH ₂ CH ₂ 0 N(iPr) ₂

 9

Scheme 7 Synthesis Route of Compound 3 and Its Phosphoramide Monomer 9 The synthetic route of Compound 4 and its phosphoramidite monomer 10 is shown in Reaction Scheme 8. Introduction of the R ⁵ R ⁶ R ⁷ Z group at the 5'-position of deoxythymidine gives compound 4, which is further converted to phosphoramidite monomer 10.

Scheme 4 and Scheme 8 Compound phosphoramidite 10 Synthesis of Compound 5 as shown in Scheme 9, as a starting material in deoxyadenosine, at its 5 '- introduction of R ⁵ R ⁶ R ⁷ Z bit group Obtained, then protected its 6-amino group, to obtain the key intermediate 5a, or, first, protect the 6-amino group of deoxyadenosine to obtain an intermediate 5b, the introduction of the R ⁵ R ⁶ R ⁷ Z group at the 5'-position gives the key intermediate 5a, 5a which is further converted to the phosphoramidite monomer 11.

 5b

Scheme 9 Synthesis route of compound 5 and its phosphoramidite monomer 11 The synthesis of compound 6 is shown in Reaction Scheme 10, starting with deoxyguanosine and introducing R ⁵ R ⁶ R ⁷ at its 5'-position. Obtained from the Z group, followed by protecting its 2-amino group to give the key intermediate 6a, or, first, protecting the 2-amino group of deoxyguanosine to give the intermediate 6b, and introducing the R ⁵ R ⁶ R ⁷ Z at the 5'-position. The group, the key intermediates 6a, 6a are further converted to the phosphoramidite monomer 12.

Scheme 10 Synthesis route of compound 6 and its phosphoramidite nitrogen monomer 12 A fourth aspect of the invention relates to the synthesis, utilization of a nucleic acid sequence comprising monomers 1-6

DM solid phase synthesis by phosphoramidite synthesis, the following nucleoside monomers were introduced into the 5'-end or other positions of the nucleotide sequence, the partial sequence is shown in Table 1, and the nucleoside monomer structure contained is as follows .

 For example, a solid phase synthesis using a general-purpose CPG resin, a phosphoramidite monomer 14e, and a deprotection condition of concentrated ammonia 55 X, 2 h are used. The resulting structure is 14f.

Nucleoside monomer structure for modifying nucleic acid structure Modified deoxynucleotide sequence

本发明的第五个方面涉及修饰核酸的高级结构的光谱分析， 将各个修饰核酸序列溶于緩冲液中， 利用圆二色傳仪测定它们的 特征峰形， 确定四螺旋和双螺旋结构的形成。

A fifth aspect of the invention relates to the spectral analysis of the high-order structure of the modified nucleic acid, the respective modified nucleic acid sequences are dissolved in a buffer, and their characteristic peak shapes are determined by a circular dichroism, and the four-helix and double-helix structures are determined. form.

 A sixth aspect of the invention relates to the activity of modifying the anti-HIV-1 fusion of a nucleic acid, and detecting the inhibitory activity using a cell fusion model.

 A seventh aspect of the invention relates to a compound of formula (I), a transport strategy using other nucleic acid drugs (such as s iRM, antisense nucleic acid, aptamer, ribozyme, etc.): with various cationic polymers such as cationic lipids A complex formed by plastids; combined with PEG, cholesterol, ligands of target cell surface receptors, etc., to improve the transport efficiency of such nucleic acid drugs.

An eighth aspect of the invention relates to a pharmaceutical composition comprising a nucleic acid of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. In one embodiment, the composition further includes other A drug that treats viral infections. In one embodiment, the virus is in particular an HIV-1 virus.

 The nucleic acid structure of the present invention can be used either in itself or in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt of the nucleic acid structure of the formula (I) includes a conventional salt formed with a pharmaceutically acceptable inorganic or organic base. Examples of suitable base addition salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, trimethylamine, triethylamine, tripropylamine, tributylamine, hydrazine, Ν'-dibenzylethylenediamine, a salt formed from chloroprocaine, choline, diethanolamine, ethylenediamine, guanidine-methylglucamine, and procaine. When referring to the nucleic acid structure of the present invention, the nucleic acid structure of the formula (I) and pharmaceutically acceptable salts thereof are included.

 The nucleic acid structure of the formula (I) may also form a solvate such as a hydrate, an alcohol or the like. In general, for the purposes of the present invention, solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms.

 The pharmaceutically acceptable carrier or excipient as used herein includes any and all solvents, diluents or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, and the like, which are suitable as the particular dosage form desired. Thickeners or emulsifiers, solid binders, lubricants, etc. Various carriers or excipients for formulating pharmaceutically acceptable compositions are disclosed in Remington's Pharmaceutical Sciences, 16th Edition, EW Mart in (Mack Publ i shing Co., Eas ton, Pa., 1980). A well-known technique for its preparation is hereby incorporated by reference in its entirety. In addition to any conventional carrier medium that is incompatible with the compounds of the present invention, for example, by creating any undesirable biological effects, or otherwise interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, it is within the scope of the present invention application.

Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycerol, Sorbic acid or potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolytes such as fish oil Protein, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polypropylene-block copolymer, Lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; scutellaria powder; malt Gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; Such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solution; Non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; colorants, release agents, coatings, and the like may also be present in the composition, as judged by the formulator. Flavoring agents, flavoring and perfuming agents, preservatives and antioxidants.

 A ninth aspect of the invention relates to the use of the nucleic acid structure of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a viral infection. In one embodiment, the virus is HIV-1 virus.

 A tenth aspect of the invention relates to a method of treating a viral infection, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a nucleic acid structure of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the virus is an HIV-1 virus. Example

Example 1. Synthesis of nucleoside monomer 16c and its phosphoramidite monomer 16c-p

NCH ₂ CH ₂ CO', N(i-Pr) ₂

 16c-p

(i) TBDPS-CI, imidazole, in DMF, at r.t;

(ii) (Ν〇〇Η ₂ 〇Η ₂ 〇)[( ^μ Ρ0 ₂ Ν] ₂ Ρ, (i-Pr) ₂ EtN tetrazolium salt, in CH ₂ CI ₂ , reaction route 12 nucleus at rt Synthesis route of glycoside monomer 16c and its phosphoramidite monomer 16c-p

1-[(2-Deoxy-β-D-ribofuranosyl-5-(tert-butyldiphenylsilyl)]-5-(tert-butyldiphenylsilyloxy-propyl)-1H, 3Η -pyrimidine-2,4-dione (16c)

5 (3-hydroxypropyl)-deoxyuridine was synthesized as described in the literature 24. To a solution of 5 (3-hydroxypropyl)-deoxyuridine (0.75 g) in DMF (10 ml), EtOAc (EtOAc: EtOAc (EtOAc) Stir for 5 h and stop the reaction by adding methanol. Column chromatography gave 0.1 g of a white foamy solid, yield 37.6%. Rf = 0.3 (DCM / MeOH = 30: 1). ^ NMR (DMSO— ): δ 0.93, 0.98 (2 s, 18 H, 2 tBu), 1.54 (m, 2 H, CH ₂ C ₂ CH ₂ ) , 2.02, 2.11 (2 m, 4H, C2 ^, -2H , C^ ₂ CH ₂ CH ₂ ) , 3.43 (m, 2 H, CH ₂ CH ₂ C) 3⁄40) , 3.74 (m, 1 H, C4 ^, -H), 3.85 (m, 2 H, C5'- H ), 4.31 (m, 1 H, CS'-H), 5.36 (d, /=4.4, CS'-OH), 6.20 (t, /=6.8, Cl'-H), 7.37, 7.59 (2 m, 21 H, arom. H, C4-H) , 11.38 (s, 1 H, NH).

1 ³ C NMR (DMSO- ): δ 18.79, 23.23, 26.63, 31.08, 39.49, 63.10, 64.07, 70.25, 83.77, 86.52, 113.634, 127.90, 129.90, 135.09, 150.28, 163.21. Elemental analysis: C ₄₄ H ₅₄ N ₂ 0 ₆ Si ₂ (M 763.08), C 69.25, H 7.13, N 3.67; 1-[(2-Deoxy-β-D-ribofuranosyl-5-(tert-butyldiphenylsilyl)]-5-(3-tert-butyldiphenylsilyloxy-propyl)-1H , 3H-pyrimidine-2,4-dione 3'-[(2-cyanoethyl)-N,N-diisopropylimide] (16c-p)

16c (0.8 g, 1.52 mmol in DCM (15 ml), diisopropylamine-tetrazolium salt (0.13 g, 0.76 mmol), and phosphorylating reagent (0.5 g, 1.67 mmol). washed with NaHC0 ₃ and water, the organic phase was dried over anhydrous Na ₂ S0 _4. column chromatography, as a white foam 0.7 g, yield 55.6%. Rf = 0.5 (DCM / acetone = 15.1).

^J H NMR (DMSO-^): δ 1.00, 1.06 (2 s, 18 H, 2 tBu), 1.18 [m, 12 H, 2 CH (Cff ₃ ) ₂ ] , 1.62, 2.13 {2 m, 6 H, N[C (CH ₃ ) ₂ 〗 ₂ , 0CH ₂ C) 3⁄4CN, 5-CH ₂ C^ ₂ CH ₂ } , 2.45, 2.63 (2 m, 2 H, C2'H), 3.46-3.94 (m, 8 H, 5-C) 3⁄4CH ₂ C) 3⁄4, 0C) 3⁄4CH ₂ CN, C5' — H), 4.09 (m, 1 H, 4'H), 4.63 (t, /=4.0, CS'-H), 6.35 (t, /=8.0, Cl'-H), 7.26-7.66 (m, 21 H, arom. H, C4-H), 8.09 (s, 1 H, NH). ³¹ P NMR (CDC1 ₃ ): 149.08, 149.11.

 Example 2 Synthesis of Nucleoside Monomer 15c and Its Phosphoramidite Monomer 15c-p

 15c-p

(i) TBDPS-CI, imidazole, in DCM, under r.t.

(ii) (NCCH ₂ CH ₂ 〇) [(i-Pr) ₂ N] ₂ P, (i-Pr) ₂ EtN Tetrazolium salt, in CH ₂ CI ₂ , reaction route 13 at rt Synthesis route of body 15c and its phosphoramidite monomer 15c-p 1-[(2-Deoxy-β-D-ribofuranosyl-5-(tert-butyldiphenylsilyl)]-5-(2-tert-butyldiphenylsilyloxy-ethyl)-1H , 3H-pyrimidine-2, 4-dione (15c)

5-(tert-Butyldiphenylsilyloxy-ethyl)-deoxyuridine was synthesized as described in the literature 24. 5-(tert-Butyldiphenylsilyloxy-ethyl)-deoxyuridine (0.9 g, 1.76 mmol) was dissolved in DCM (30 mL). Toluene (0.24 g, 3.53 mmol) TBDPS-CI (0.53 g, 1.94 mmol) was then added in portions. After completion of the reaction, the solution was concentrated and purified by column chromatography to yield white white solid (yield:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: , 18 H, 2 tBu), 2.08 (m, 2 H, C5-C^ ₂ CH ₂ ) , 2.34 (m, 2 H, C2 ^, -H), 3.63 (m, 1H, C5-CH ₂ C ₂ 0 ), 3.74 (m, 1 H, C4 ^, -H), 3.86 (m, 2 H, C5'- H), 4.28 (m, 1 H, C3,-H), 5.32 (d, /=4.4, CS '-OH), 6.19 (t, 7=6.4, Cl'-H), 7.34-7.64 (m, 21 H, arom. H, C4-H) , 11.33 (s, 1 H, NH) „ ¹³ C NMR (DMSO- ): δ 18.66, 26.53, 30.06, 39.50, 54.89, 61.72, 64.04, 70.20, 83.74, 86.45, 110.44, 127.71, 129.91, 133.51, 134.94, 136.87, 150.25, 162.80. Elemental analysis: C ₄₃ H ₅₂ N ₂ 0 ₆ Si ₂ (M 749.05), C 68.95, H 7.00, N 3.74; </ RTI></RTI> C 68.73, H 6.89, N 3.45.

1-[(2-Deoxy-β-D-ribofuranosyl-5-(tert-butyldiphenylsilyl)]-5-(tert-butyldiphenylsilyloxy-ethyl)-1H, 3H -pyrimidine-2,4-dione V-[(2-cyanoethyl)-N,N-diisopropylimide] (15c-p)

Compound 15c (0.8 g, 1.52 mmol) was dissolved in DCM (15 ml), diisopropylamine-tetrazolium salt 0.13 g (0.76 leg ol), phosphorylating reagent (0.5 g, 1.67 mmol), stirring 2h. This solution was washed with NaHC0 ₃ solution and brine, the organic phase was dried over anhydrous Na ₂ S0 _4. Separation by column chromatography gave a colorless foamy solid 0.7 g. Yield 55.6% ₀ Rf = 0.5 (DCM / acetone = 15.1). ^ NMR (CDCU : δ 1.0-1.59 {m, 30 H, 2 tBu, N [CH (Cff ₃ ) ₂ ] ₂ } , 2.06 (m, 1 H, C2, -HJ, 2.36-2.63 (m, 5 H , C5-CH ₂ , 0CH ₂ C CN, Cl'- ,), 3.55-3.94 (m, 8 H, C5-CH ₂ C^0, N[C (CH ₃ ) ₂ 〗 ₂ , 0C^ ₂ CH ₂ CN, C5,-H), 4.11 (m, 1 H, C4'- H), 4.58 (m, 1 H, C3'- H), 6.30 (m, 1H, Cl'-H), 7.26-7.68 ( m, arom. H, C4-H) „ ³¹ P NMR (CDC1 ₃ ): 148.98, 149.49. Example 3 Synthesis of nucleoside monomer 14c and its phosphoramidite monomer 14c-p

 (i) TBDPS-CI, imidazole, in DCM, under r.t.

(ii) (NCCH ₂ CH ₂ 0)[(i-Pr) ₂ N] ₂ P, (i-Pr) ₂ EtN tetrazolium salt, in CH ₂ CI ₂ , reaction route 14 at rt Synthesis route of body 14c and its phosphoramidite structure 14c-p

1-[(2-Deoxy-β-D-ribofuranosyl-5-(tert-butyldiphenylsilyl)]-5-(tert-butyldiphenylsilyloxy-methyl)-1H, 3Η -pyrimidine-2,4-dione (14c)

5-(tert-Butyldiphenylsilyloxymethyl)-deoxyuridine was synthesized as described in the literature 24. Add 5-(tert-butyldiphenylsilyloxymethyl)-deoxyuridine (0.8 g, 1.62 leg ol) to DCMQO ml), add imidazole (0.22 g, 3.24 mmol) to this solution, and divide TBDPS-C1 (0.49 g, 1.78 mmol) was added in batches. After completion of the reaction, column chromatography was carried out to give a white foamy solid, 0.8 g, yield 67.2% „ Rf=0.3 (DCM/MeOH =30: 1). NMR (DMSO-^): δ 0.88, 0.95 (2 s, 19 H, 2 tBu), 2.04-2.33 (m, 2 H, C2 ^, -H), 3.68-3.89 (m, 3 H, C -H, CS'-H), 4.16-4.32 (m, 3 H, C5-CH ₂ 0, CS'-H), 5.38 (d, /=4.4, CS'-OH), 6.16 (t, 7=6.8, Cl '-H), 7.34-7.69 (m, 21 H, arom. H, C4-H), 11.43 (s, 1 H, NH) „ ¹³ C NMR (DMSO- ): δ 25.48, 26.91, 41.29, 65.20, 66.67, 71.65, 73.36, 77.12, 109.76, 174.16 elemental _{analysis: C 42 H 50 N 2 O} 6 Si 2 (M 735.03), C 68.63, H 6.86, N 3.81; measured value, C 68.66, H 6.64, N 3.59. .

1-[(2-Deoxy-β-D-ribofuranosyl-5-(tert-butyldiphenylsilyl)]-5-(tert-butyldiphenylsilyloxy-methyl)-1H, 3H -pyrimidine-2,4-dione V-[(2-cyanoethyl)-N,N-diisopropylimide] (14c-p)

Compound 14c (0.5 g, 0.98 mmol) was dissolved in DCM (15 ml), and diisopropylamine-tetrazolium salt (0.1 g, 0.5 leg ol) and phosphorylating reagent (0.5 g, 1.67 mmol) . Completion of the reaction by TLC, washed with NaHC0 ₃ solution and brine successively. The organic phase was dried over anhydrous Na ₂ S0 _4. Column chromatography gave 0.5 g of a white foamy solid, yield 56.1% </ </ RTI></RTI> Rf = 0.7 (DCM/acetone = 15.1). NMR (CDCU: δ 0.96-1.19 {m, 30 H, 2 tBu, N [CH (Cff ₃ ) ₂ ] ₂ } , 2.04 (m, 1 H, C2, -HJ, 2.47 (m, 2 H, 0CH ₂ C ₂ CN) , 2.61 (m, 1 H, Cl'- ,), 3.56- 3.83 (m, 6 H, N [C#(CH ₃ ) ₂ ] ₂ , OC ₂ CN, C5,-H), 4.13 (m, 1 H, C4 ^, -H), 4.40 (s, 2 H, C5- CH ₂ ) , 4.51 (m, 1 H, C3'- H), 6.21 (m, 1 H, Cl'-H), 7.26-7.64 (m, 21 H, arom. H, C4-H) , 8.08 ( s, 1H, NH) ³¹ P NMR (CDC1 ₃ ): 149.36, 149.79. Example 4 Synthesis and Properties of Nucleic Acid Structures

1. Synthesis, purification and identification of sequences All sequences were synthesized using a solid phase phosphoramidite triester method using an ABI 392 RNA/DNA synthesizer according to conventional procedures. The synthesized sequence was purified by high performance liquid chromatography. Finally, desalting treatment was carried out using a solid phase extraction column and identified by MALDI-TOF, wherein the sequence with the DMT group was identified by ESI-MS.

 The solid phase phosphoramidite triester method mainly comprises the following steps: (1) Deprotection: removing the DMT group on the 5'-hydroxyl group of the terminal nucleotide of the resin beads (CPG) with trifluoroacetic acid to release the hydroxyl group; (2) Condensation: The phosphoramidite monomer is activated with tetrazolium to form a reactive intermediate of phosphoramidite tetrazolium, and undergoes nucleophilic reaction with the 5'-hydroxyl group of the terminal nucleotide of the resin bead; (3) Blocking: To avoid the occurrence of side reactions, the unreacted hydroxyl group in the coupling reaction is blocked with an acetyl group; (4) Oxidation: The phosphoramidite monomer is converted into a stable phosphoramide monomer, and proceeds to the next cycle.

The synthesized sequence was removed in concentrated ammonia water for 2.5 h, removed from the CPG, and the protective group of the natural monomer was removed. The sequence containing the TBDPS protecting group was detected (LK-CW-G02 to LK). - CW- G15). Ammonia water was distilled off under reduced pressure, and dissolved with a small amount of water to obtain a colorless, transparent aqueous solution. All sequences were purified by HPLC (column: Diamons il, C18, 5 μ, 250 x 4. 6 mm) in a 0.1 M ammonium acetate buffer solution with a gradient of 30 min CH ₃ CN from 20 % to 100%. Table 2 shows the retention times of the partial sequences.

 The retention time of the nucleic acid structure was purified by HPLC.

编号 序列（5'-3') t_R (min)

Numbering sequence (5'-3') t _R (min)

 LK-CW-G07 d(i<feGGGAG) 11.67

 LK-CW-G13 d(i^cGGGAG) 16.8

 LK-CW-G14 d(iJcGGGAG) 17.2

 LK-CW-G15 d(i<fcGGGAG) 18.5

 LK-CW-G16 dUTGGGAG) 17.6 and 19.8 Most of the sequences have two distinct peaks, and the two are identified by mass spectrometry as the same compound. It is presumed that the former is a single-stranded oligodeoxynucleotide and the latter is a G-tetra-helical structure. . The purified sequence was desalted by HPLC (color column: MACHEREY-NAGEL, C18, 5μ 150 χ 4.6 mm). All sequences were identified by mass spectrometry. Table 3 shows the results of mass spectrometry identification of partial sequences.

 Table 3 MALDI-TOF determination results of nucleic acid structure

利用圆二色谱确定修饰核酸的高级结构 将 2 μ M的核苷酸序列溶于緩冲液中，在室温下测定高级结构 的形成和特征峰。如图 1可见， LK- CW-01至 LK- CW- 07均显示出平 行四螺旋结构的特征 CD谱。 峰的位移是因为修饰结构而引起的， 但不影响整体的四螺旋结构的形成。 图 2为双螺旋结构 D01+D02 的 CD谱， 具有双螺旋结构的特征峰。 实施例 6 修饰核酸的抗 HIV-1融合活性评价研究

Determination of the advanced structure of modified nucleic acids by circular dichroism The 2 μM nucleotide sequence was dissolved in a buffer, and the formation and characteristic peaks of the high-order structure were measured at room temperature. As can be seen from Fig. 1, both LK-CW-01 to LK-CW-07 show characteristic CD spectra of parallel four-helix structures. The displacement of the peak is caused by the modified structure, but does not affect the formation of the overall four-helical structure. Fig. 2 is a CD spectrum of a double helix structure D01+D02, having a characteristic peak of a double helix structure. Example 6 Evaluation of Anti-HIV-1 Fusion Activity of Modified Nucleic Acids

 Luciferase cell fusion experiments were used to detect cell fusion mediated by HIV-1. The TZM-bl cells were first plated on a 96-well plate, 50 μl/well of cell suspension at a concentration of 500,000 / ml, and cultured for 24 hours under conditions of 37. The HL2/3 cells were then plated on 96-well plates plated with TZM-bl cells, 50 μl/well of cell suspension at a concentration of 1.7 million/ml, and column 12 of the 96-well plate was used as the lowest signal blank. HL2/3 cells were not added and replaced with 50 μl/well of medium. Then add the sample to be tested (the sample is diluted 4 times in a round bottom 96-well plate to a 10th hole, and 11 and 12 holes contain only the medium as a control. The sample is prepared before adding HL2/3 cells. ). The two cells were fused at 37 for 6-8 h, then the cells were lysed, and 25 μl / 孑L of cell lysate was taken to the corresponding well on a brick plate (cos tar, Whi te polys tyrene; Corning incorporated, USA), and then added. 40 μl/well of fluorescent reagent was detected in a microplate reader. The activity data of some nucleic acid structures are shown in Table 4 and Table 5. Inhibition of modified deoxynucleotide sequences HIV-1 fusion activity

LK-CW-G05 d(iJaGGGAG)₄ 1.44

LK-CW-G05 d(iJaGGGAG) ₄ 1.44

LK-CW-G06 d(i<feGGGAG) ₄ 0.89

LK-CW-G07 d(i<f«GGGAG) ₄ 0.62

LK-CW-G13 d( cGGGAG) ₄ 4.97

LK-CW-G14 d(i/cGGGAG) ₄ 1.42

LK-CW-G16 dU7GGGAG) ₄ 2.02

D01+D02 2.28 Modification of modified DM double helix structure HIV-1 fusion activity

编号 序列（5'-3') ic₅。

Numbering sequence (5'-3') ic ₅ .

 LK-CX-D13 5' -d (DMT-iJaAGCGTATGCAGATTT 9.04 ± 0.194

 3' -d (iJaTCGCATACGTCT

 LK-CX-D25 5, -d (DMT- aAGCGTATGCAGATTT 7.59 soil 0.17 y -d (KaTCGCATACGTCT ^

 LK-CX-D08 5' -d (DMT-iJaAGCGTATG) -3' 1.29 + 0.15 LK-CX-D09 y -d (i aTCGCATAC) -5'

 LK-CX-D10 5'-d (DMT-lAGCGTATG)-3, 3.20± 1· 15 LK-CX-Dll 3'-d(lTCGCATAC)-5'

 LK-CX-D24 5, -d (DMT- AGCGTATG) -3, 3.08 + 0.36 LK-CX-Dll -d (KaTCGCATAC) -5'

 LK-CX-D26 5' -d (DMT-i-aTGCGTATG) -V 1.62 + 0.75 LK-CX-Dll -d (KaTCGCATAC) -5'

 LK-CX-D18 AAA-AGCGTATGCAGA)-5' ND

 TCGCATACGTCT) -3'

 LK-CX-D19 GAG-AGCGTATGCAGA)-5' ND

 C TCGCATACGTCT) -3'

 LK-CX-D22 5, -d (GAGCi^aAi-aGGC) -3' 2.94 ± 0.78 LK-CX-D23 3'-d (CTCGAi-aACCG)-5'

 LK-CX-D08 5' -d (DMT-iJaAGCGTATG) -3' 1.29 + 0.15 LK-CX-D09 y -d (iJaTCGCATAC) -5'

LK-CX-D12 y 4.91 + 0.62

LK-CX-D10 5' -d (DMT-i-eAGCGTATG) -V 3.20 ± 1.15 LK-CX-Dll ' -d (KaTCGCATAC) -5' Numbering sequence (5'-3') ic ₅ .

 LK-CX-D15 5' -d (DMT-i-eAGCGTATGAC) -3' 1.90 ± 0.37 LK-CX-D16 3'-dU TCGCATACTG)-5'

LK-CX-D12 5' 4.91 + 0.62

 LK-CX-D13 5, -d (DMT-iJ«AGCGTATGCAGATTTv 9.04土 0· 19

 3' - (iJaTCGCATACGTCT . ^ - ^

 LK-CX-D14 5, -d (DMT-iJ«AGCGTATGCAGAAGCTTTT 8.31 + 0.72

 3' - (iJaTCGCATACGTCTTCGA References:

 (1) Andrew, N. L., Chaires, J. B., Robert, D. G. and John, 0. T. (2008) Stability and kinetics of G-quadruplex structures. Nucleic Acids Res., 36, 5482-5515.

 (2) Dapic, V., Abdomerovic, V., Marrington, R., Peberdy J., Rodger, A., Trent, J. 0. and Bates, PJ (2003) Biophysical and biological properties of quadruplex oligodeoxyribonucleo tides. Nucleic Acids Res., 31, 2097-2107.

 (3) Esposito, V. , Gal leone, A. , Mayol, L. , Oliviero, G. , Virgilio, A. and Randazzo, L. (2007) A topological classification of G-quadruplex structures. Nucleosides Nucleotides & Nucleic Acids , 26, 1155 1159.

 (4) Webba da Silva, M. (2007) Geometric formalism for DM quadruplex folding. Chemistry, 13, 9738 9745.

(5) Sarah, B., Gary, NP, Pascale, H., Alan, KT And Stephen, N. (2006) Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res., 34, 5402-5415.

 (6) Max, A. K. (2001) Quadruplex Structures in Nucleic Acids. Biopolymers (Nucleic Acid Sciences), 56, 123-146.

 (7) Li, Y. and Breaker, R. R. (1999) Deoxyr ibozymes: new players in the ancient game of biocatalys is. Curr. Opln. Struct. Biol., 9, 315 323.

 (8) Chen, Q., Kuntz, I. D. and Shafer, R. H. (1996) Spectroscopic recognition of guanine dimeric hairpin quadruplexes by a carbocyanine dye. PTOC. Natl. Acad. Sci. USA" 93, 2635 2639.

 (9) Paula, B., Jean-Louis, M. and Danzhou, Y. (2007) Quartets in G-major. EMBO reports, 8, 1003-1010.

 (10) Max, A. K. (2001) Quadruplex Structures in Nucleic Acids. Biopolymers (Nucleic Acid Sciences), 56, 123-146.

 (11) Bock, L. C., Griffin, L. C., Latham, J. A., Vermaas E. H. and Toole, J. J. (1992) Selection of Single-Stranded DNA Molecules That Bind and Inhibit Human Thrombin. Nature, 355, 564-566.

(12) Ojwang, J. 0., Buckheit, RW, Pommier, Y., Mazumder, A., De Vreese, K., Este, JA, Reymen, D., Pal lansch, LA, Lackman-Smith, C. , Wallace, TL, De Clercq, E., McGrath, MS and Rando, RF (1995) T30177, an oligonucleotide stabilized by an intramolecular guanos ine octet, is a potent inhibitor of laboratory strains and clinical isolates of human immunodeficiency Virus type 1. Antimicrobial Agents and Chemotherapy, 39, 2426-2435.

 (13) Wyatt, JR, Vickers, TA, Roberson, JL, Buckheit, RW, Jr., Klimkait, T., DeBaets, E., Davis, PW, Rayner, B., Imbach, JL and Ecker, DJ (1994) Combinatorial ly selected guanos ine-quartet structure is a potent inhibitor of human immunodeficiency virus

Envelope-mediated cell fusion. Proc. Natl. Acad. Sci. , 91, 1356-1360.

 (14) Wyatt, J. R., Davis, P. W. and Freier, S. M. (1996) Kinetics of G—Quartet—Mediated tetramer formation.

Biochemistry, 35, 8002-8008.

 (15) Furukawa, H., Momota, K., Agatsuma, T., Yamamoto, I., Kimura, S. and Shimada, K. (1994) Mechanism of inhibition of HIV-1 infection in vitro by Guanine - rich oligonucleotides Modified at the 5' terminal by

Dimethoxytrityl residue. Nucleic Acids Res. , 22,

5621-5627.

 (16) Hotoda, H., Momota, K., Furukawa, H., Nakamura, T., Kaneko, M., Kimura, S. and Shimada, K. (1994)

Biologically Active 01 igodeoxyribonucleo tides. 2:

Structure activity relationships of anti-HIV-1

Pentadecadeoxyribonucleo tides bearing

 5' -end-modifications. Nucleosides Nucleotides, 13,

1375-1395.

(17) Furukawa, H., Momota, K., Agatsuma, T., Yamamoto, I. , Kimura, S. and Shimada, K. (1995) Inhibition of HIV-1 infection in vitro by short Guanine— rich oligonucleotides modified at the 5' -terminal with dimethoxytrityl residue. Ant i sense Res. Dev. , 5, 89.

 (18) Furukawa, H., Momota, K., Agatsuma, T., Yamamoto, I., Kimura, S. and Shimada, K. (1997) Identification of a phosphodiester hexanucleotide that inhibits HIV-1 infection in vitro on covalent Linkage of its 5' -end with a dimethoxytrityl residue. An tl sense Nucleic Acid Drug Dev. 7, 167-175.

 (19) Hitoshi, H., Makoto, K., Rika, K., Masakatsu, K. and Kaoru, S. (1998) Biological ly active

Oligodeoxyribonucleo tides. 5. ¹ 5' -End-Substituted

d (TGGGAG) possesses ant i -human immunodeficiency virus type 1 activity by forming a G-quadruplex structure. J. Med. Chem. , 41, 3655-3663.

 (20) Makoto, K., Rika, K., Hitoshi, H. and Toshinori, 0. (1998) Biologically Active 01 igodeoxyribonucleo tides, part 11: The lease phos pha t e-mod i f i ca t i on of

 Quadrup 1 ex-f orming hexadeoxyr ibonucleot ide TGGGAG, bearing V -and 5' -end-modification, with anti-HIV-1 activity. Bioorg. & Med. Chem., 6, 2469-2475.

 (21) Synthesis, biophysical characterization, and anti-HIV activity of glyco- conjugated

G-quadruplex-forming oligonucleotides. Biocon juga te Chem. 19, 607-616. (22) Jennifer, D., Luigi, P., Eva, E., Luigi, M., Giovanni, DF, Lorenzo, DN, Concetta, G. and Daniela, M. (2007) 5' -modified G-quadruplex Forming

Oligonucleotides endowed with anti-HIV activity: synthesis and biophysical properties. Bioconjugate Chem. , 18, 1194-1204.

 (23) Robert, W. D. and Didier, T. (2000) The plasma membrane as a combat zone in the HIV battlefield. Genes & Develop. , 14, 2677-2688.

 (24) Di. Zhang, Liang. Xu, Xia. Wei, Yamin. Li, Junl in He, and Kel iang Liu Hydroxyl-functional DM: an efficient orthogonal protection strategy and duplex stability Nucleosides, Nucleotides, & Nucleic Acids, 2009 , 28, 924-942.

Claims

Rights request A nucleic acid structure of the formula (I) or a pharmaceutically acceptable salt or solvate thereof,

 (I)  among them, R ^{1 is} attached at the 5'-end of the nucleotide sequence, independently selected from the nucleoside monomer structure of Formula 1-6, which is 3'-hydroxy or 5'-hydroxy with the nucleoside Acid sequence

R ^{2 is} attached at the y-terminus of the nucleotide sequence, independently selected from the group consisting of: hydrogen atom, methylphosphoryl group, 2-chlorophenylphosphoryl group, methylthiophosphoryl group, methylphosphono group, methylthio group Phosphono, phenylphosphono, 2-hydroxyethylphosphoryl, 2-hydroxyethylthiophosphoryl, phenylphosphoryl, 4-chlorophenylphosphoryl, 2-hydroxy-3-acetamido-propyl base; R ³ is absent or is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogen a C1-4 alkyl group substituted with an amino group or a C1-4 alkoxy group or a halogen atom, a substituted or unsubstituted aryl group and a substituted or unsubstituted aralkyl group; X is selected from the group consisting of an oxygen atom, a sulfur atom, an NH ₂ , NH and a C1-6 alkylene chain; wherein when X is NH ₂ , R ³ is absent; R ⁴ is absent or is selected from a hydrogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylamino group, a halogen atom, and a C1-substituted by an amino group or a C1-6 alkoxy group or a halogen atom. a 6 alkyl group, a substituted or unsubstituted aryl group and a substituted or unsubstituted aralkyl group; Y is selected from the group consisting of an oxygen atom, a sulfur atom, NH ₂ , NH, a hydrogen atom, a fluorine atom and a C1-6 alkylene group, wherein when Y is H, NH ₂ or F, R ³ is absent; 13⁄4 and m ₂ represent the number of structural units containing bases B ⁴ and B ¹ -B ² -B ³ - B ⁵ , each independently being 1-15; B ¹ , B ² , B ³ , B ⁴ and B ⁵ are bases on a nucleotide sequence, each independently selected from the group consisting of A, G, C, T, mC, mG and unnatural bases, and combinations thereof; X ¹ is absent or is selected from a C1-6 alkylene group, a C2- 6 alkenylene group and a C2- 6 alkynylene group, wherein the C1-6 alkylene group, the C2- 6 alkenylene group and the C2- 6 group One or more methylene groups in the alkynylene group are optionally replaced by an oxygen atom, a sulfur atom, an amide group or an ester group; X ² is absent or is selected from an oxygen atom, CH ₂ , NH and a sulfur atom; Or X ¹ and X ² may together form a methyleneoxy group, an ethyleneoxy group, a propyleneoxy group, a 1-propoxy group, a 3-propyleneoxy group or a 1-propenyloxy group; X ^{3 is} selected from the group consisting of CH and a nitrogen atom;  Z is selected from a carbon atom or a silicon atom; R ^5, R ⁶ and R ⁷ are the same or different, are each independently selected from C1-4 alkyl, R ⁸ is unsubstituted or monosubstituted or polysubstituted by C6-20 aryl group, and R ⁸ is unsubstituted or monosubstituted Or a multi-substituted sulfhydryl group; R ⁸ is C1-4 alkyl, C1-4 haloalkyl, halogen atom, nitro, cyano, amino, C1-4 alkoxy, C1-4 alkylthio, substituted or unsubstituted aryl, aryloxy base, Aralkyloxy; Or R ⁵ , R ⁶ and R ⁷ and Z are selected from the group consisting of fluorenyl, P ton, preferably 9-fluorenyl, 9-fluorene; In the nucleoside monomer 1-3, R ⁵ , R ⁶ , R ⁷ and Z are bonded to S'-O or X ² R ⁷  R, |— The groups _R ^{Z_ are the} same or different and may exist simultaneously or separately, at this time

When the nucleoside monomer 1-3 has no group at the 5' position R ⁷ When R ^Z —, nucleoside monomers 1-3 are linked to the nucleotide sequence by a 5'-hydroxyl group. The nucleic acid structure of the formula (I) according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein 13⁄4 and 111 ₂ are each independently from 1 to 10; wherein n is preferably from 1 to 6, more preferably from 1 to 4, most preferably from 1 or 2. The nucleic acid structure of the formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R ^{1 is} attached at the 5'-end, independently selected from the monomer structure 1-6; R ^{2 is} attached at the 3'-end and is independently selected from the group consisting of: a hydrogen atom, a methylphosphoryl group, a 2-chlorophenylphosphoryl group, a methylthiophosphoryl group, a 2-hydroxyethylphosphoryl group, and a 2-hydroxy-3 group. - acetamido-propyl. The nucleic acid structure of the formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein X ¹ is C1-6 alkylene, C1-6 alkenylene or C1-6 alkynylene, wherein one or more methylene groups in the C1-6 alkylene group are optionally replaced by an oxygen atom; X ² is an oxygen atom, CH ₂ , NH or a sulfur atom; X ¹ and X ^{2 together} form a methyleneoxy group, an ethyleneoxy group, a propyleneoxy group, a -1-propynyloxy group, or a propylene-1-oxy group; X ³ is CH or a nitrogen atom. The nucleic acid structure of the formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein X and R ^{3 together} form an OH, SH, methoxy, ethoxy, propoxy or benzyloxy group. The nucleic acid structure of the formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein Y and R ^{4 together} form a hydroxyl group, a fluorine atom, a hydrogen atom, a methoxy group, an ethoxy group, a propoxy group, a methoxymethyleneoxy group, a methoxyethyleneoxy group, an ethoxymethylene group , methylamino or ethylamino. 7. A four-helical structure formed by the nucleic acid structure of the general formula (I) according to claim 1, wherein the nucleic acid structure contains one to four GGG or GGGG fragments. The four-helical structure of claim 7, wherein the nucleic acid structure of the formula (I) contains one to four GGG or GGGG fragments selected from d (TGGGAG) ₄ , d (GGGTG) ₄ , d (TGGGA) 4, d (TGGGA) ₄ , d (TGGGA) ₄ , d (TGGGA) ₄ , d (TGGGA) ₄ or d (TGGGA) ₄ . 9. A triple helix structure formed by the nucleic acid structure of the general formula (I) according to claim 1, wherein the base composition of the nucleic acid structure is a total oxime or a perpyrimidine composition. 10. A double helix structure formed by the nucleic acid structure of formula (I) according to claim 1, wherein the base of the nucleic acid structure is a random combination of natural bases. 11. The double helix structure of claim 10, wherein the base of the nucleic acid structure is a random combination of natural bases selected from the group consisting of d (TCTGCATG) and d (CATGCAGA). The nucleic acid structure of the formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein  The nucleoside monomers of the formula 1-6 are each independently selected from the group consisting of 14a-14f, 15a-15e and 16a-16e. 13. A pharmaceutical composition comprising the nucleic acid structure of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or form . 14. The pharmaceutical composition of claim 13, further comprising a medicament for treating a viral infection. 15. The pharmaceutical composition of claim 14, wherein the virus is an HIV-1 virus. 16. Use of the nucleic acid structure of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a viral infection. 17. The use of claim 16, wherein the virus is an HIV-1 virus. 18. A method of treating a viral infection, the method comprising administering a need for such treatment A therapeutically effective amount of the nucleic acid structure of the formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof. 19. The method of claim 18, wherein the virus is an HIV-1 virus, 20. a phosphoramidite structure of a nucleoside monomer of the formula 7-12,

 8 9

 10 1 1 1 2  among them X ¹ , X ² , X ³ , R ⁵ , R ⁶ , R ⁷ and Z are as defined in claim 1; R ⁹ is a protecting group for the 6-position amino group of adenine and its analogs; R ¹ " is a protecting group for the 2-amino group of guanine and its analogs.