WO1996003133A1

WO1996003133A1 - Novel anti-hiv drug

Info

Publication number: WO1996003133A1
Application number: PCT/JP1995/001456
Authority: WO
Inventors: Akira Kaji; Hideko Kaji
Original assignee: Akira Kaji
Priority date: 1994-07-22
Filing date: 1995-07-21
Publication date: 1996-02-08

Abstract

An anti-HIV drug containing an active ingredient comprising at least one member selected from among dito octabase phosphodiester-linked and phosphorothioester-linked oligoribonucleotides represented by the tetrabase homologues represented by the following formulae: (III) GpGpGpGp, (VII) pGpGpGpG, (XI) GsGsGsGp, (XVII) pGsGsGsG, (XXI) GsGsGsG, wherein G represents a guanosine structure; p represents a phosphate residue forming an ester linkage with an adjacent G; and s represents a phosphorothiophosphate residue forming a phosphorothioester linkage with an adjacent G.

Description

Specification

New anti-HIV agent

Industrial applications

The present invention relates to a phosphodiester-binding type or a hoshortiester-binding type that exhibits excellent antiviral activity against diseases caused by HIV (Human Immunodeficiency Virus). The present invention relates to an anti-HIV drug containing a ribonucleotide as an active ingredient.

Kyokyo technology

According to the conventional knowledge of DNA homologues, it has been reported by Agra et al. That the 15-base and 20-base phosphorothioate conjugates have an inhibitory effect on HIV growth, and that the effect is evident. It is reported that it is not dependent on the type of base, because it is a homooligomer with a length of 15 bases. In addition, its efficacy is based on the fact that it is a long-length homooligomeric molecule, which favors reverse transcriptase type II and competes with HIV nucleic acids. It is reported that it was estimated. (Pro Natl. Acad. Sci. USA, 85, 7079, 1988).

In addition, according to McCra et al., It has been reported that a 28-base deoxycitrine phosphochorate conjugate has an inhibitory effect on HIV proliferation (Proc. Natl. Acad. Sci. USA, 84, 7706, 1987).

In addition, according to the conventional knowledge of oligoribonucleotides, a 20-base 2'-o-methylinoino by Shibahara et al. It has been shown that the synhosphoroate conjugate has an inhibitory effect on HIV growth (Nucleic Acid Res., 17, 239, 1989), It has been reported that riadenin-polyuridine also has an inhibitory effect on HIV proliferation (AIDS Res. Human Retroviruses. 8, 285, 1992). Both have 14-28 bases or more long-chain nucleotides, so there is a problem in preparing them, and they were administered in vivo. There is also a problem in terms of absorption and stability in cases.

In order to solve such a problem, the present inventor has conducted various studies on the reduction of the molecular weight of an oligonucleotide compound having an inhibitory effect on the growth of HIV, and has first made a short 4 to 8 nucleotides. It was found that chain oligodoxyguanylic acid has an HIV growth inhibitory effect.

As a result of further studies, the present inventors have found that a new short-chain oligoriboguanylic acid having 2 to 8 bases has an inhibitory action on HI proliferation. The present invention is based on such findings.

That is, the present invention also provides a phosphodiester-bonded oligoribonucleotide represented by the formulas (I) to (XXΠI) described in the following items (a) to (e). Or one or more selected from hoshortiester-bonded oligoribonucleotides as an active ingredient. It provides anti-HIV drugs.

E) E represented by any of the following formulas (I) to (IV) An anti-HIV agent characterized in that it contains one or more selected from among the phosphodiester-binding oligoribonucleotides as an active ingredient. .

G p up (: I)

U P Lr p Up (I D

G p u p u p up (I I I)

υ υ ρ υ ρ ρ ρ

(In each formula, G represents a guanosine structure, ρ represents a phosphoric acid residue forming an ester bond with an adjacent G, and ρ represents the 3 ′ Forms a monoester bond with the hydroxyl group at the 3'-position of the terminal G, and each ρ located between the two Gs is the G on the left side in the formula. Is an ester bond with the 3'-hydroxyl group, and G on the right-hand side is an ester bond with the 5'-hydroxyl group.)

Mouth) One or more kinds selected from phosphodiester-bonded oligonucleotides represented by any of the following formulas (V) to (VIII) An anti-HIV agent characterized as containing it as an active ingredient.

p G p G (V)

p G p G p G (VI)

p G p G p G p G (VI I)

p G p G p G p G p G (VI II) (In each formula, each G and p are as defined above, and the left terminal p is the 5'-position of the terminal G. It forms a monoester bond with a hydroxyl group.) C) one selected from the group consisting of a hosphoroester bonded type oligoribonucleotide represented by any of the following formulas UX) to (XV), or An anti-HIV agent characterized by containing two or more as active ingredients.

G s G p (IX) G s G s G p (X)

G s G s G s G p (XI) G s G s G s G s G p (XI I) G s G s G s G s G s G p (XI II) G s G s G s G s G s G sp (IV) G s G s G s G s G s G s G s G p (XV) (wherein each G and p represent the same as above, and s is The s represents a phosphorothiophosphoric acid residue that forms a phosphorothioester bond with an adjacent G, and each s is 3 'to the G on the left side in the formula. The hydroxyl group and the right-hand side G form an ester bond with the 5′-position hydroxyl group, respectively).

(Ii) one selected from the phosphoholoester-bonded oligoribonucleotides represented by any of the following formulas (XVI) to (IXX) Or, an anti-HIV agent characterized by containing two or more kinds as an active ingredient.

p G s G s G (XVI)

p G s G s G s G (XVI I) p G s G s G s G s G (XVI II) p G s G s G susus G (I ΛΛ) (In each formula, each G, p and s represent the same as above.)

E) It is selected from the phosphoric ester bonded type oligonucleotide represented by any of the following formulas (XX) to (XXII I) An anti-HIV agent characterized in that it contains one or more kinds as an active ingredient.

G s G s G (XX)

G s G s G s G (X I)

G s G s G s G s G (XXII)

G s G s G s G s G s G (XXI I I)

(In each formula, each G and s represent the same as above.) Hereinafter, the present invention will be described in detail.

The oligoribonucleotides represented by the above formulas (I) to (XXIII), which are the active ingredients of the anti-HIV agent of the present invention, are generally used for the synthesis of oligoribonucleotides. Can be synthesized by conventional techniques (Scaringe et al., Nucleic Acids

Res. 18 5433; Damha and Ogilvie, Methods in Mol. Biol.

20 81; see Eckstein, Ann. Rev. Biochem 54 367) ₀ A preferred representative synthetic method for the synthesis of the compounds of the present invention is

[Synthesis method A] to [Synthesis method E] are exemplified below.

(Synthesis method A)

2_ [2— (4,4'-measurement re-till oxy) ethyl sulphur on the contact pore glass (CPG) as a support (Honyl) Succinoyl long-chain alkylamino group attached (P35, Glen Research User Guide (Glen Lab. Riso, 44901 Falcon Place, Sterling, VA 20166)), and then the protecting group 4,4'-dimethylmethoxytrityl group is treated with trichloroacetic acid or the like. Except that tetrazole was used as a condensing agent, and an amidite reagent in which the amino group of a guanylate group as a monomer was protected with an isobutyl group, (5 ′ 1 o — Dimethyl citrine) 1 2'— o — (t — Butyrene dimethyl) Ribonucleoside 3 '— N, N — Diy Condensation of pill (cyanoethyl) phosphoamidite. Thereafter, the phosphorus portion is oxidized using iodine, leading to a phosphoric acid triester body. After the above reaction is repeated until the desired chain length is obtained, each internucleotide is subjected to ammonia treatment by a triester. It converts to physical strength, and is extracted from the support. At the same time, the base is deprotected, and the tetra-N-butylammonium derivative is removed. A method in which the hydroxyl group at the 2'-position is deprotected by a light treatment to obtain the desired 3'-terminal phosphorylated oligoribonucleotide.

(Synthesis method B)

In the case of solid-phase synthesis by the phosphoramidite method, guanosine with a protected functional group is applied to a support such as control-bore glass (CPG). Prepare the bound product and add 4,4'-dimethoxytrityl group, which is a protecting group for the 5'-hydroxyl group of this nucleotide, to trichloroacetic acid, etc. Amidite reagents in which tetrazole is used as a condensing agent and the amino group of the guanylate group as a monomer is protected with an isobutyl group,

(5'—o—dimethycitrite) 1 2'—o— (t—butyl Condensation of phos-homidite is condensed. 3 ′ —N, N-diisopropinole (cyanoethino) To prevent the synthesis of by-products, the unreacted 5'-hydroxyl group is acetylated with acetic anhydride, N-methylimigzole, or the like. After that, the phosphorous portion is oxidized using iodine to lead to a phosphoric acid triester body. After the above reaction was repeated until the desired chain length was reached, a phosphorylation reagent was added at the 5'-terminal, and (2—cyanoethoxy) 1-2— (2'- o -4, 4'-dimension kits (Horn & Urdea (Tetrahedron Letters 27 4705; Uhlmann

& En gels (See Tetrahedron Letters 27 1023)) _{0 After the} terminal phosphorus is oxidized to form a phosphoric acid triester using ammonia, each is treated with ammonia. The internucleotide is converted from a tri-ester to a di-ester, which is cut out from the support and, at the same time, deprotects the base moiety. La-N-butyrene ammonium fluoride is used to deprotect the 2'-hydroxyl group, and the target 5'-terminal phosphorylated oligoribonucleic acid How to make it a Creature.

(Synthesis method C)

2-[2-(4, 4'-dimensions) with control-pore glass (CPG) as a support [Honyl] A succinyl compound with a long-chain alkylamino group bonded to it (see the above-mentioned publication of Glen Research Laboratories) was prepared. 4, 4 '— Trimethyl dimethyl It is removed with chloroacetic acid, etc., and tetrazole is used as a condensing agent, and the amino group of guanylate group as a monomer is replaced with an isobutyl group. Protected amidite reagent, (5'-o—dimethoxycitryl) 1-2'-o— (t-butyltin dimethyltrisilyl) ribonucleic acid Leoside 3'-N, N — Condensates diisobrovinore (cyanethyl) phosphoramigite. Thereafter, the phosphorus portion is oxidized using iodine to lead to a phosphoric acid triester body. Next, the 5'-protecting group (DMTR) of this guanylic acid is removed with trichloroacetic acid, and the second amidate protecting the functional group of guanylic acid is removed. The reagents are condensed as above. After that, sulfuration of the second lin is performed using tetraethyl uranium dissolving fluid, and the phosphatography is performed. Lead to the body. Thereafter, the condensation of guanylic acid and the sulfurization of the phosphorus moiety are repeated until the desired length is reached, and finally, each nucleotide is also converted. The ammonia processing converts each internucleotide from a tri-ester to a di-ester, and converts the internucleotide into a diester. For the purpose of deprotection of the base moiety and deprotection of the hydroxyl group at the 2'-position by treatment with tetra-N-butylammonium fluoride. 'The method of using a phosphorylated oligoribonucleotide at the terminal end.

(Synthesis method D)

In this section, the hosihomidite method for obtaining oligoribonucleotides having hosphoester bonds is described. Prepare guanosine, whose functional group is protected, bound to a support such as control pore glass (CPG). The 4,4'-dimethyloxytrityl group, which is a protecting group for the hydroxyl group at the 5'-position of this nucleoside, is removed with trichloroacetic acid or the like, and guanylate is removed. Amidite reagent in which the amino group of the acid base is protected with an isobutyl group, (5'-o-dimethoxycitryl 1 2 ')-o-1 ( t — Butinore di-methyl thiol) Ribonucleoside 3'-N, N — Diisopropynole (cyanoethyl) Condensed using tetrazole as a condensing agent. In order to prevent the synthesis of by-products, the unreacted 5'-hydroxyl group is acetylated with acetic anhydride, N-methylimidazole, or the like. After that, the rind is sulfurized using tetraethyl uranium disulphide, which leads to the hoshorochiotriester body. After the above reaction is repeated until the target chain length is reached, the 5'-terminal is finally deprotected, and a phosphorylation reagent (2—cyanoethoxy) is used. 1 2 — (2 '— ο — 4, 4' — Dimethyloxyl thiocyanuryl sulfonyl) Ethoxy N, N — Diisopropirua mino The phosphine is condensed (see Tetrahedron Letters, supra), and the terminal phosphorus is oxidized to form a phosphoric acid triester using ammonium chloride. The processing converts the triester into a diester, which is cleaved from the support and deprotected at the same time as the base. The hydroxyl group at the 2'-position is deprotected by the treatment with dimethylphenol, and the phosphorylated phosphorylated phosphate at the 5'-terminal is targeted. A force method that makes it a polygon.

(Synthesis method E) This section describes a preferred phosphoramidite method applied to the synthesis of compounds of formulas (XX)-(XXII). Prepare a substance bonded to a support such as trawl dope glass (CPG) and prepare 4,4'-dimethoxy which is a protecting group for the 5'-hydroxyl group of this nucleoside. The trimethyl group is removed with trichloroacetic acid or the like, and the amidate reagent in which the amino group of the guanylate group is protected with the isopropyl group, (5 '— o — Dimethyl citrine) 1 2'-o-(t-butyl dimethylsilyl) Ribonucleoside 3 '-N, N- Condensation of disopropinole (cyanoethyl) phosphamide using tetrazole as a condensing agent. To prevent this, the unreacted 5'-hydroxyl group is acetylated with acetic anhydride, N-methylimidazole, etc. After that, tetraethylate Sulfuration of the phosphorous part is performed using a urethium sulfide and the sulfide is led to a phosphoric acid triester body. After repeating the process until the chain length reaches a certain length, ammonia processing is used to remove each nucleotide from the triester body to the polyester. The product is converted to a thiol form, cut out from the support and deprotected at the same time as the base, and treated at the 2'-position by tetra-N-butylammonium fluoride treatment. A method for deprotecting hydroxyl groups to obtain the target oligoribonucleotide.

Experimental example

Next, the present invention will be described in more detail with reference to experimental examples. However, the gist of the present invention is not limited to these experimental examples. Absent.

, MT — 4 cell (T cell line) anti-virus virus (HIV) activity test〉

Various types of phosphodiester-bonded or phosphodiester-bonded types that have been serially diluted in advance are included. 96--4 cells were spread on a 96-well microplate with a volume of 6 x 10 ⁴ cells / well, and then used for AIDS virus (HIV-1 (IΠB; about 50 TCI). (50% cultured cell infection concentration) / well] and cultured for 5 days at 37 ° C and 5% carbon dioxide. To determine the inhibition of cell damage due to infection, the cells were cultured for 5 days. It was determined by measuring the cells by the MTT method.

Table 1 shows the results.

In the table, the meanings of P and s in the formulas for each of the displayed oligonucleotides have the same meanings as defined above, and G represents guanosine, A represents adenosine, C represents cytidine, and U represents peridine.

ED _S0 (50% cytotoxicity inhibitory concentration)

G p G 100 g / m 1 or more

G p G p G 100 ί g / m 1 or more

G p G p G p G 100 // g / ml or more

(40% failure suppression)

A p A p A p A p 100 g / m 1 or more U p U p U p U p 100 g Z m 1 or more C p C p C p C p 100 g no ml or more p G p G 100 β g / ml that's all

(25% failure suppression)

G p G p 22.

G s G p 28.5 g ml

G s G s G p \. 2, β g ml p G s G s G 5.g ml

G s G s G 16.6 g ml

G p G p G p 20.2 g ml p G p G p G 45.1 β g ml p G p G p G p G 15.3 g ml

G s G s G s G p 0.7 g ml

G p G p G p G p 2.2 β g ml p G s G s G s G \. \ G ml

G s G s G s G 4.0 g ml

G p G p G p G p G p 1.6 g ml p G s G s G s G s G s G 0.9 / g ml G s G s G s G s G s G 2.Q μg / ml

G s G s G s G s G s G p 2.3 ug / ml

GsGsGsGsGsGsGsGp \ .μ.g / ml As shown in Table 1, phos, which is an active ingredient of the anti-HIV agent of the present invention, Anti-HIV activity is observed even with 2 nucleotides of phospho- or phospho-ester-bound oligoribonucleotides, while excellent anti-HIV activity is observed with 3 to 8 nucleotides. It was shown to have HIV effects. Furthermore, none of the oligoribonucleotides showed cytotoxicity at a concentration of 100 g / ml. On the other hand, phosphodiester-linked oligoguanic acid in which the terminal G was not phosphorylated had no effect at all with a few bases, and showed a slight effect with four bases. In addition, no effect was observed with any of the four bases of 3′-terminal phosphorylated phosphodiester-bonded oligoadenylic acid, citidic acid, and peridinic acid. On the other hand, in the 3'-terminal or 5'-terminal phosphorylated phosphodiester-bonded type and the phosphoroester-type bonded oligoguanylic acid, it is effective. The gender is recognized to be outstanding.

Regarding the safety of various oligoguanylic acids, which are the active ingredients of the anti-HIV agent of the present invention, the mice were administered intravenously at 20 mg / kg to mice using 4-base bonds. The safety was confirmed. In another study, it was confirmed that each of these substances did not cause death even after oral administration of 100 mg Z kg. The novel anti-HIV agent according to the present invention is particularly useful as a therapeutic agent for retroviral infections such as AIDS, and is formulated into a tablet using a pharmaceutical carrier, and is used as a tablet. It can be made into oral dosage forms such as capsules, capsules, granules, syrups, and powders, and parenteral dosage forms such as injections, infusions, and suppositories.

The dosage form is not specified, and an appropriate dosage form may be selected and used as needed, such as tablets, capsules, and granules. And parenteral administration agents such as injections, suppositories and the like.

The amount required as an oral preparation varies depending on the age, weight, and degree of disease of the patient, and the dosage for adults is usually 0.1 g to 6 g divided into several times a day. Take it.

In order to prepare the above-mentioned oral preparations such as tablets, capsules, granules, etc., for example, starch, lactose, sucrose, mannitol, carboxymethyl Cellulose and inorganic salts can be used, and are produced according to a conventional method.

In this type of preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity enhancer, a flavoring agent, a coloring agent, a fragrance, etc. are appropriately selected and used in addition to the above-mentioned excipients. You can do it. Specific examples are as follows.

(Binder)

Starch, dextrin, arabia rubber powder, gelatin, hydroxypropinorestin, methinoresenolose, carboxy Methylcellulose sodium, hydroxypropylcellulose, crystal cellulose, ethylcellulose, Livininore Senororose, McGorgo Norre.

(Disintegrant)

Starch, hydroxypropyl start, carboxy methylcellulose rosam, carboxymethylcellulose calcium Um, carboxymethylcellulose, low-substituted hydroxypropyl cellulose.

(Surfactant)

Sodium leuryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80.

(Lubricant)

Talc, roux, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, polyethylene glycol.

(Fluidity enhancer)

Light gay anhydride, dry aluminum hydride gel, synthetic anolemminium gaylate, magnesium magnesium acid.

The oligoribonucleotides represented by the formulas (I) to (XXm) according to the present invention include suspensions, emulsion liquids, syrups, and elixirs. It can also be administered as a preparation, and each of these dosage forms can contain a flavoring agent and a coloring agent.

The amount required as a parenteral preparation varies depending on the age, weight, and degree of the disease of the patient, but it is usually 1 to 1 for the above-mentioned oligoribonucleotides per day for adults. It is about 00 mg and is administered by intravenous injection, intravenous drip infusion, subcutaneous injection, or intramuscular injection. This parenteral preparation can be manufactured by a conventional method. In this case, the diluents are generally distilled water for injection, physiological saline, aqueous solution of glucose, vegetable oil for injection, sesame oil, racquet oil, soybean oil, and grease. Corn oil, propylene glycol, polyethylene glycol, etc. can be used. Also, fungicides, preservatives, and stabilizers can be added as needed. From the viewpoint of stability, this parenteral preparation is filled into a vial or the like, then frozen, the water is removed by ordinary freeze-drying technology, and the product is lyophilized immediately before use. Thus, the solution can be reconstituted from the lyophilized product at the time of use. Upon formulation, if necessary, an isotonic agent, a stabilizer, a preservative, an analgesic agent and the like can be appropriately added.

Examples of other parenteral preparations include liquid preparations for external use, coating preparations such as soft blue, suppositories for rectal administration, etc., all of which can be manufactured by a conventional method. it can.

Example

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the Examples described below. Example 1

Prescription:

① Crystal cellulose 84.5 parts by weight

② Magnesium stearate 0.5 parts by weight

③ Carboxy Methyl Cellulose

Calcium 5 parts by weight GGG p G D. 10 Heavy noise l Total 1 GO Parts by weight According to the above formula, ① and ② and a part of are mixed until homogeneous, compression molded, crushed, and then crushed. The remaining amount of (1) and (3) were added to and mixed, and the mixture was compression-molded with a tableting machine to obtain a tablet of 200 mg per tablet.

This one tablet contains 20 mg of GpGpGpGp. This tablet is taken in several doses of 4 to 8 tablets daily for an adult.

Example 2

Prescription:

①Crystal cellulose 34.5 parts by weight

② 10% Hydroxy pill

50% by weight of phenolic ethanol solution

(3) Cal box

Calcium 5 parts by weight

0.5% by weight magnesium stearate

⑤ P G P G P G ID G _ 10

Total 100 parts by weight According to the above formula, ① and ② are mixed until homogenous, kneaded by a conventional method, extruded and dried and crushed by a granulator. After that, ③ and ④ were mixed with the mixture, and the mixture was compression-molded with a tablet machine to obtain a tablet of 200 mg per tablet.

This one tablet contains 20 mg of pGpGpGpG. Adults take this tablet in 4 divided doses 8 times a day for adults. Used.

Example 3

Prescription:

① Suitable for distilled water for injection M

② sugar cane 200 mg

③ G p G p G p G p 10 mg

Total volume 15 ml

For (1), (2) and (3) were dissolved, and the mixture was injected into a 5 ml sample, and sterilized by heating at 121 ° C for 15 minutes to obtain an injection.

In addition, compounds other than the compounds described in each of the above examples according to the present invention can also be made into various dosage forms according to the formulations shown in the above respective examples.

The invention's effect

The novel anti-HIV agent according to the present invention is effective for the treatment of diseases caused by HIV (AIDS virus), AIDS and ARC.

Claims

The scope of the claims

1. One or two selected from the phosphodiester-bound oligoribonucleotides represented by any of the following formulas (I) to (IV): An anti-HIV agent characterized by containing at least one species as an active ingredient.

G p G p (I)

G p G p G p (I I)

G p u p G p G p (I I I)

G p G p G p G p G p (IV)

(In each formula, G represents a guanosine structure, p represents a phosphoric acid residue forming an ester bond with an adjacent G, and p at the right end represents the 3′-position. It forms a monoester bond with the hydroxyl group at the 3'-position of the terminal G, and each p located between the two Gs is the same as the G on the left side in the formula. Represents an ester bond with the 3′-hydroxyl group, and G on the right-hand side forms an ester bond with the 5′-hydroxyl group).

2. One or two selected from phosphodiester-bonded oligoribonucleotides represented by any of the following formulas (V) to (VI II). An anti-HIV agent characterized by containing at least one species as an active ingredient.

p G p G (V)

p G p G p G (VI)

p G p G p G p G (VI I)

p G p G p G p G p G (V 11 I)

(In each formula, each G and p represent the same as above. The left end P forms a monoester bond with the 5 'hydroxyl group at the 5' end G).

3. It is selected from the following phosphoric acid ester-bound oligoribonucleotides represented by any of the following formulas (IX) to (XV). An anti-HIV agent characterized by containing one or more kinds as an active ingredient.

us G p (IX) G s G s G p (X) G s G s G s G p (XI) Li s G s G s G s G p (XI I) sus G s G s G sup (XI 1 ]) Lr sus G s G s G susup

G s G s G s G s G s G s G s G p (XV) (where each G and p represent the same as above, and s is Represents a phosphorothiophosphoric acid residue forming a phosphoroester bond, and each s is 3 to the left G in the formula. The 'hydroxyl group and the right-hand G are each an ester bond with the 5'hydroxyl group).

4. A type selected from the group consisting of a hosphoroester ester-type oligoribonucleotide represented by one of the following formulas (XVI) to (IXX). Or, an anti-HIV agent characterized by containing two or more kinds as an active ingredient.

P U S U S Lr (XVI)

p G sususu (XVI 1) p G s G s G s G s G (XVI II) p G s G s G s G s G s G (IXX)

(In each formula, each G, p, and s represent the same as above.)

5. It is selected from the group consisting of a phosphoroester bonded type oligoribonucleotide represented by any of the following formulas (XX) to (XXI II). An anti-HIV agent characterized by containing one or more kinds as an active ingredient.

G s G s G (XX)

G s G s G s G (XXI)

G s G s G s G s G (XXII)

G s G s G s G s G s G (XXI II)

(In each formula, each G and s represent the same as above.)