WO2022223007A1

WO2022223007A1 - Antiviral polypeptide compound

Info

Publication number: WO2022223007A1
Application number: PCT/CN2022/088266
Authority: WO
Inventors: 王潮; 刘克良; 王欢; 李晴
Original assignee: 中国人民解放军军事科学院军事医学研究院
Priority date: 2021-04-23
Filing date: 2022-04-21
Publication date: 2022-10-27
Also published as: CN117098560A

Abstract

An antiviral polypeptide compound, and particularly, a single-component double-target anti-HIV drug, a composition comprising same, and a use thereof.

Description

Antiviral Polypeptide Compounds

technical field

The present disclosure relates to an antiviral polypeptide compound. In particular, the present disclosure relates to a single-component dual-target anti-HIV drug, compositions comprising the same, and uses thereof.

Background technique

AIDS is mainly caused by human immunodeficiency virus (HIV) infection. Since the first case of AIDS was discovered, the global death toll has exceeded 35 million; there are still 37.7 million infected worldwide; in 2020, the number of new infections will reach 1.5 million. AIDS has a very high ultimate fatality rate, and there is still no cure and lack of effective vaccines. Drug treatment is still the only effective method at present. Based on the study of the virus life cycle, four classes of anti-HIV drugs have been developed, namely: entry inhibitors, reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors. Among them, entry inhibitors act in the early stage of viral infection and can effectively prevent HIV from invading host cells. Compared with antiviral drugs that must enter the host cell to play a role, entry inhibitors block the initial stage of HIV invading cells, which can keep the virus out of normal cells and prevent the virus from integrating into the human genome after entering the cell. Theoretically, it is superior to other "infection first and then treatment" drugs.

The invasion of HIV into host cells involves three sequential steps: first, the viral envelope glycoprotein surface subunit gp120 binds to the CD4 receptor molecule on the host cell; then, gp120 binds to the CCR5 or CXCR4 coreceptor on the host cell; finally, Exposure of the transmembrane subunit gp41 of the viral envelope glycoprotein initiates the viral–host cell membrane fusion process mediated by it. Gp41 contains functional domains such as N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR). During the fusion process, the NHR and CHR interact to form a six-helix bundle (6-HB) and release energy that drives the virus into the host cell. For the above-mentioned links, 4 HIV entry inhibitors have been approved by the US FDA, they are: gp120-targeting adsorption inhibitors Trogarzo and Fostemsavir, CCR5-targeting inhibitors The coreceptor inhibitor Maraviroc (Maraviroc) and the fusion inhibitor Enfuvirtide (also known as T20) that interfere with the formation of viral 6-HB.

HIV's high variability allows it to develop resistance to most therapeutic drugs. T20 is a polypeptide derived directly from the native CHR sequence of viral gp41. Although the natural structure satisfies the target's requirements for the drug structure to the greatest extent, it also leads to low resistance of T20 to gp41 mutation, which makes it easy to develop drug resistance. Mutation of a single residue in the target region can lead to resistance of the virus to T20. Studies have shown that HIV can use both CCR5 and CXCR4 to invade host cells. HIV strains that use the former to enter host cells are called R5 tropic viruses; HIV strains that use the latter to invade host cells are called X4 tropic viruses. AIDS patients in different infection periods, HIV tropism will change. Maraviroc targets CCR5, so it is only effective against R5-tropic viruses. The transformation of HIV co-receptor from CCR5 to CXCR4 is one of the main reasons for Maraviroc resistance.

In summary, based on innovative ideas, a new structural type of HIV entry inhibitor with high efficiency and low toxicity was constructed to fight against the rapidly emerging T20-resistant strains, and at the same time to solve the problem of viral tropism changes after receiving CCR5 inhibitors. The problem of drug resistance has become a key problem that needs to be solved urgently in the current field of anti-AIDS drug research.

SUMMARY OF THE INVENTION

The inventors of the present disclosure have obtained a novel single-component dual-target anti-HIV drug through ingenious design, both for HIV laboratory virus strains (BaL and IIIB), and HIV clinical isolates (including T20 drug resistance) strains), all exhibit low _EC50 values, provide high anti-HIV activity while reducing toxicity to the organism, and can be used against various HIV strains (including T20-resistant strains); in addition, also It solves the problem of drug resistance of HIV strains due to changes in tropism after receiving CCR5 inhibitors (ie: effective for HIV strains with X4 tropism), has good clinical application prospects and market value, and brings patients Gospel.

According to one embodiment of the present disclosure, a compound of formula (I) may be provided

or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein

P represents a fusion inhibitory polypeptide targeting gp41;

SM stands for CCR5 small molecule antagonist;

L ₁ is optional and represents a flexible link arm;

L is optional and represents a flexible link arm _;

A represents one or more amino acid residues;

α is optionally present and is selected from the group consisting of acetyl, maleyl, succinyl, tert-butoxycarbonyl, benzyloxycarbonyl, dansyl or other hydrophobic or macromolecular carrier groups, and is associated with the amino terminal residue of P. base direct connection;

β is optionally present, selected from amino or other hydrophobic groups or macromolecular carrier groups, and is directly attached to the carboxy-terminal residue in A;

When L ₁ is present, the amino-terminal residue of A is directly linked to L ₁ ; when L ₁ is absent, the amino-terminal residue of A is directly linked to P;

When L2 is present, the side chain of _A is directly connected to L2 _; when L2 is not present, the side chain of _A is directly connected to SM.

According to one embodiment of the present disclosure, there may be provided a composition comprising a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.

According to one embodiment of the present disclosure, a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a composition according to the present disclosure may be provided in the manufacture of a compound for the prevention or treatment of AIDS use in medicines.

Description of drawings

Figure 1 shows a schematic diagram of the synthesis of compounds of formula (I) in one embodiment according to the present disclosure. In order to show the reaction process and connection of each part more clearly, the groups involved in the reaction are highlighted in Figure 1. For example, the -(CH ₂ ) ₄ NH ₂ directly connected to Lys in B is actually - in Lys (CH ₂ ) ₄ NH ₂ group, the -NH- and -C=O- directly connected to Lys in D are actually -NH- and -C=O- groups in Lys, which is understood by those skilled in the art This representation is not misunderstood.

Figure 2 shows a schematic diagram of the synthesis of polypeptide resins in the Examples.

Figure 3 shows: Matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS) results of compound 1-1.

Detailed ways

Unless otherwise stated, all numbers used in this specification and claims to indicate amounts, concentrations, ratios, weights, percentages, technical effects, etc., should in any event be understood to be represented by the terms "about" or "approximately" retouch. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations. Unless otherwise defined, terms used herein have the meanings commonly understood by those skilled in the art. It may vary depending upon the desired properties and effects sought to be obtained by the present disclosure to those skilled in the art, and each numerical parameter should be interpreted in accordance with the number of significant digits and conventional rounding methods or as understood by those skilled in the art.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values set forth in the specific examples are provided as precisely as possible. Any numerical value, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

As used herein, "compound" is intended to encompass both small and macromolecular compounds, for example, including but not limited to amino acids, polypeptides, proteins, carbohydrates, lipids, 4-piperidine-1-propanamines, 1 , 4-disubstituted piperazine compounds, tropane compounds and their conjugates.

As used herein, "compounds of formula (I)" (synonymous with "compounds of formula (I)," "compounds of the present disclosure") are intended to encompass compounds of formula (I) per se, as well as isotopic labels, optical Isomers, geometric isomers, tautomers or mixtures of isomers.

The term "isotopic label" means an isotopically labeled compound in which any atom of the compound has been replaced by its isotopic atom. Examples of isotopes suitable for inclusion in compounds of formula (I) include isotopes of hydrogen such as 2H(D) and 3H(T); isotopes of carbon such as 11C, 13C and 14C; isotopes of chlorine such as 36Cl; fluorine isotopes of iodine such as 18F; isotopes of iodine such as 123I and 125I; isotopes of nitrogen such as 13N and 15N; isotopes of oxygen such as 15O, 17O and 18O; and isotopes of sulfur such as 35S.

The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center may exist in R configuration or S configuration, and various isomers thus constituted are optical isomers Construct. Optical isomers include all diastereomers, enantiomers, mesomers, racemates or mixtures thereof. Optical isomers can be separated, for example, by chiral chromatography columns or by chiral synthesis.

The term "geometric isomer" means that when a double bond exists in a compound, the compound may exist as cis isomer, trans isomer, E isomer and Z isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers or mixtures thereof.

The term "tautomer" refers to an isomer resulting from the rapid movement of an atom in a molecule between two positions. Those skilled in the art can understand that tautomers can be transformed into each other, and may reach an equilibrium state and coexist in a certain state. "Compounds of formula (I)" as described herein also encompass any tautomer of compounds of formula (I).

The compounds of formula (I) may exist in unsolvated as well as solvated forms, including hydrated forms, which are encompassed within the scope of this disclosure.

Compounds of formula (I) may exist in different crystalline or amorphous forms, all of which are encompassed within the scope of this disclosure.

Unless otherwise defined herein, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art.

As used herein, the expression "A and/or B" includes three situations: (1) A; (2) B; and (3) A and B. The expression "A, B and/or C" includes seven situations: (1) A; (2) B; (3) C; (4) A and B; (5) A and C; (6) B and C ; and (7) A, B, and C. The meaning of similar expressions can be deduced in the same way.

As used herein, "pharmaceutically acceptable salts" include acid addition salts and base addition salts. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate , camphor sulfonate, citrate, cyclohexylamine sulfonate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexa Fluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, 2-isethionate, lactate , Malate, Maleate, Malonate, Mesylate, Methylsulfate, Naphthate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Orotate , oxalate, hexadecate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glucarate, stearate, salicylate, tannin, tartrate , tosylate and trifluoroacetate. Suitable base addition salts are formed from bases which form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Hemi-salts of acids and bases, such as hemi-sulfate and hemi-calcium salts, can also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of compounds of formula (I) are known to those skilled in the art.

As used herein, "prodrug" refers to a compound of formula (I) converted to a compound of formula (I) by reaction with enzymes, gastric acid, etc. in vivo under physiological conditions, eg, by oxidation, reduction, hydrolysis, etc., each catalyzed by an enzyme Derivatives.

As used herein, "metabolite" refers to all molecules derived from a compound of formula (I) in a cell or organism (preferably human).

As used herein, the term "optionally present" means that it may or may not be present.

As used herein, the term "independently of each other" means that multiple events do not affect each other. For example, "X and Y are independently selected from any of a, b, c, d, e, f, g" means that X can be any of a, b, c, d, e, f, g, and Y It can also be any one of a, b, c, d, e, f, and g. The selection of X and the selection of Y can be the same or different, and the two do not interfere with each other.

As used herein, a numerical range represents a recitation of all integers within that range, and ranges are presented only as a shorthand notation. In addition, numerical ranges also encompass any sub-range thereof, and each sub-range is also considered to be disclosed herein.

As used herein, a "gp41-targeting fusion-inhibiting polypeptide" refers to any polypeptide that is capable of binding to gp41 in HIV, thereby inhibiting fusion of HIV with the target cell membrane, such as fusion-inhibiting polypeptides derived from gp41 CHR, including but not Limited to T20, C34, T1249, T1144, AP3, HP23, P52, Sifuvirtide and its derivatives, etc.

As used herein, "CCR5 small molecule antagonist" refers to any small molecule compound that can block the binding of gp120 to CCR5, thereby inhibiting HIV entry into target cells, including but not limited to Maraviroc, TAK compounds (eg TAK- 779, TAK-652, TAK-220, etc.), Aplaviroc, Cenicriviroc and its derivatives, etc.

As used herein, "flexible connecting arm" refers to any flexible arm known to those skilled in the art, which is easily bent and deformed, thereby changing the relative positional relationship of the objects connected at both ends. Examples of any flexible arms include, but are not limited to: polyethylene glycols with an amino group at one end and a carboxyl group at the other end; ethanolamine; 6-aminocaproic acid; β-alanine; 3-mercaptopropionic acid; flexible peptides such as ( GGGGS) _y , (GGGS) _y , (GSG) _y , (GSGSG) _y , etc.

As used herein, "amino acid residue" refers to: when an amino acid is linked to other compounds (which may be amino acids or other molecules) through chemical bonds, part of its groups are lost due to participating in the formation of linkages, and the remaining An amino acid moiety is an amino acid residue.

Similarly, the residue of a compound refers to: when the compound is connected with other compounds (which may be the same or different from the compound) through chemical bonds, some of its groups are lost due to participating in the formation of the connecting bond, and the remaining groups are lost. Compound moieties are compound residues.

As used herein, an "amino-terminal residue" refers to a group located at the amino-terminus of an amino acid, polypeptide or protein.

As used herein, a "carboxy terminal residue" refers to a group located at the carboxy terminus of an amino acid, polypeptide or protein.

As used herein, "hydrophobic group" refers to any hydrophobic group known to those skilled in the art that has no affinity for water, is insoluble in water, or has minimal solubility. Hydrophobic groups include but are not limited to C10-C30 hydrocarbon groups; hydrocarbon groups containing aryl, ester, ether, amine, amide and other groups; hydrocarbon groups containing double bonds; polyoxypropylene groups; long-chain perfluoroalkyl groups; polysilicon oxyalkyl, etc.

As used herein, "macromolecular carrier group" refers to, including but not limited to, lipid-fatty acid conjugates, polyethylene glycol, carbohydrate-based groups.

As used herein, "side chain" refers to: in an amino acid, other groups other than amino, carboxyl, and hydrogen atoms are attached to the central carbon atom.

As used herein, if the A1 group in compound A and the B1 group in compound B can react to form a chemical bond, both the A1 group and the B1 group can be referred to as "active groups". Examples of reactive groups include, but are not limited to, amino groups, carboxyl groups, amide groups, alkynyl groups, hydroxyl groups, and the like.

As used herein, a "single-component dual-target drug" refers to a drug formed by chemically linking a compound M targeting a first target and a compound N targeting a second target.

The present disclosure provides a single-component dual-target anti-HIV drug, wherein a compound targeting gp41 and a compound targeting CCR5 (more specifically, a fusion inhibitory polypeptide targeting gp41 and a small molecule antagonist of CCR5) are linked by a chemical bond . In combination with multiple drugs (eg, combined administration of multiple single-target HIV drugs) or multi-component co-formulations (ie, containing multiple chemical entities in one administration unit (eg, one tablet or one injection)) In contrast, the single-component dual-target anti-HIV drug can not only inhibit multiple links of the viral replication cycle, reduce the viral load, but also improve the patient's compliance, and also reduce the interaction between drugs and their effects. It has the toxic and side effects brought by it, and has uniform pharmacokinetic properties, does not have the problem of dose and proportion of combined drugs, and has a significantly reduced EC ₅₀ value, which can reduce the dosage and improve the therapeutic effect. In short, the single-component dual-target anti-HIV drug of the present disclosure has high efficiency and low toxicity, and can effectively overcome HIV drug resistance.

Accordingly, the present disclosure can provide a compound of formula (I)

P represents a fusion inhibitory polypeptide targeting gp41;

SM stands for CCR5 small molecule antagonist;

L ₁ is optional and represents a flexible link arm;

L is optional and represents a flexible link arm _;

A represents one or more amino acid residues;

In some embodiments, P can be a fusion inhibitory polypeptide derived from gp41 CHR. In some embodiments, P can be any of T20, C34, T1249, T1144, AP3, HP23, P52, Sifuvirtide, and derivatives thereof. In some embodiments, P can be SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 , SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 12 or SEQ ID NO: 13 targeting gp41 fusion inhibitory polypeptide. In some embodiments, P can be SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:12 Or the fusion inhibitory polypeptide targeting gp41 shown in SEQ ID NO: 13. In some embodiments, P can be the targeted gp41 set forth in SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7 fusion inhibitory polypeptide

The corresponding relationship between the sequence number (SEQ ID NO:) used in this paper and the specific sequence is shown in the following table, wherein the polypeptides shown in SEQ ID NOs: 1-13 are all acetylated at the amino terminus and amidated at the carboxyl terminus.

In some embodiments, SM may be selected from the residues of 4-piperidine-1-propylamines, 1,4-disubstituted piperazines, or tropanes.

In some embodiments, SM can be selected from the residues of the following compounds:

Wherein Ac represents acetyl; Me represents methyl; R ₁ represents -F, -Cl, -CN, -CF ₃ or -SO ₂ CH ₃ ; R ₂ represents (CH2) _p N ₃ , p is between 1-10 the integer.

In some embodiments, L ₁ , L ₂ can independently represent -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)- (sequence from carboxyl terminus to amino terminus, and called PEG-type flexible linking arm, the same below), m is an integer between 1-30, n is an integer between 1-3; or L ₁ , L ₂ can independently represent (GGGGS) _y , (GGGS) _y , (GSG) _y or (GSGSG) _y , where y is an integer between 1 and 6.

In some embodiments, L ₁ and L ₂ can independently represent -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, wherein m is between 1-30, Between 1-28, between 1-26, between 1-24, between 2-30, between 2-28, between 2-26, between 2-24, between 3-30, between 3- Integer between 28, 3-26, 3-24, 4-30, 4-28, 4-26, 4-24, n is 1, 2 or 3.

In some embodiments, L ₁ , L ₂ can independently represent (GGGGS) _y , (GGGS) _y , (GSG) _y or (GSGSG) _y , where y is an integer between 1-6. In some embodiments, L ₁ , L ₂ may independently represent (GGGGS) _y , (GGGS) _y , (GSG) _y or (GSGSG) _y , where y is an integer between 1-4. In some embodiments, L ₁ , L ₂ may independently represent (GGGGS) _y or (GSGSG) _y , where y is an integer between 1-4. In some embodiments, L ₁ , L ₂ may independently represent (GSGSG) _y , where y is an integer between 1-4.

In some embodiments, both L ₁ and L ₂ may be present. In some embodiments, only one of L ₁ and L ₂ may be present. In some embodiments, only L ₁ of L ₁ and L ₂ may be present. _In some embodiments, only L2 _of _L1 and L2 may be present.

In some embodiments, only L ₁ may be present of L ₁ and L ₂ , and L ₁ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 4 An integer between -24 and n is an integer between 1-3. In some embodiments, only L ₁ may be present of L ₁ and L ₂ , and L ₁ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 4 , where n is 1, 2 or 3. In some embodiments, only L ₁ may be present of L ₁ and L ₂ , and L ₁ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 6 , where n is 1, 2 or 3. In some embodiments, only L ₁ may be present of L ₁ and L ₂ , and L ₁ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 8 , 1, 2 or 3. In some embodiments, only L ₁ may be present of L ₁ and L ₂ , and L ₁ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 12 , where n is 1, 2 or 3. In some embodiments, only L ₁ may be present of L ₁ and L ₂ , and L ₁ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 16 , where n is 1, 2 or 3. In some embodiments, only L ₁ may be present of L ₁ and L ₂ , and L ₁ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 20 , where n is 1, 2 or 3. In some embodiments, only L ₁ may be present of L ₁ and L ₂ , and L ₁ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 24 , where n is 1, 2 or 3.

In some embodiments, only L ₁ may be present in L ₁ and L ₂ , L ₁ represents (GGGGS) _y , (GGGS) _y , (GSG) _y or (GSGSG) _y , and y is an integer between 1-6 . In some embodiments, only L ₁ may be present in L ₁ and L ₂ , L ₁ represents (GGGGS) _y , (GGGS) _y , (GSG) _y or (GSGSG) _y , and y is an integer between 1-4 . In some embodiments, only L ₁ may be present in L ₁ and L ₂ , L ₁ represents (GGGGS) _y or (GSGSG) _y , and y is an integer between 1-4. In some embodiments, only L ₁ may be present of L ₁ and L ₂ , where L ₁ represents (GSGSG) _y , and y is an integer between 1-4.

In some embodiments, only L ₂ may be present in L ₁ and L ₂ , and L ₂ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 4 An integer between -24 and n is an integer between 1-3. In some embodiments, only L ₂ may be present in L ₁ and L ₂ , and L ₂ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 4 , where n is 1, 2 or 3. In some embodiments, only L ₂ may be present in L ₁ and L ₂ , and L ₂ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 6 , where n is 1, 2 or 3. In some embodiments, only L ₂ may be present of L ₁ and L ₂ , and L ₂ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 8 , 1, 2 or 3. In some embodiments, only L ₂ may be present in L ₁ and L ₂ , and L ₂ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 12 , where n is 1, 2 or 3. In some embodiments, only L ₂ may be present of L ₁ and L ₂ , and L ₂ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 16 , where n is 1, 2 or 3. In some embodiments, only L ₂ may be present in L ₁ and L ₂ , and L ₂ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 20 , where n is 1, 2 or 3. In some embodiments, only L ₂ may be present in L ₁ and L ₂ , and L ₂ represents -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O)-, where m is 24 , where n is 1, 2 or 3.

In some embodiments, only L ₂ may be present in L ₁ and L ₂ , L ₂ represents (GGGGS) _y , (GGGS) _y , (GSG) _y or (GSGSG) _y , and y is an integer between 1-6 . In some embodiments, only L ₂ may be present of L ₁ and L ₂ , L ₂ represents (GGGGS) _y , (GGGS) _y , (GSG) _y or (GSGSG) _y , and y is an integer between 1-4 . In some embodiments, only L ₂ may be present of L ₁ and L ₂ , where L ₂ represents (GGGGS) _y or (GSGSG) _y , and y is an integer between 1-4. In some embodiments, only L ₂ may be present of L ₁ and L ₂ , where L ₂ represents (GSGSG) _y , and y is an integer between 1-4.

In some embodiments, P is a fusion inhibitory polypeptide targeting gp41 shown in SEQ ID NO: 1, and SM is

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is an integer between 6 and 12, and n is 1 , 2 or 3, y is 1, 2, 3 or 4, L ₂ is absent.

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , wherein m is 6, 8 or 12, and n is 1, 2 or 3, y is 1, ₂ , 3 or 4, L2 is absent.

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , wherein m is 6, 8 or 12, n is 2, y is 1, ₂ , 3 or 4, L2 is absent.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is an integer between 6 and 12, and n is 1 , 2 or 3, y is 1, 2, 3 or 4, L ₁ is absent.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , wherein m is 6, 8 or 12, and n is 1, 2 or 3, y is 1, 2, 3 or 4, L ₁ is absent.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , wherein m is 6, 8 or 12, n is 2, y is 1, 2, 3 or 4, L ₁ is absent.

In some embodiments, P is a fusion inhibitory polypeptide targeting gp41 set forth in SEQ ID NO: 7 or SEQ ID NO: 8, and SM is

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is an integer between 12 and 24, and n is 1 , 2 or 3, y is 1, 2, 3 or 4, L ₂ is absent.

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 12, 16, 20 or 24, and n is 1 , 2 or 3, y is 1, 2, 3 or 4, L ₂ is absent.

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , wherein m is 12, 16, 20 or 24, and n is 2 , y is 1, ₂ , 3 or 4, L2 does not exist.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is an integer between 12 and 24, and n is 1 , 2 or 3, y is 1, 2, 3 or 4, L ₁ is absent.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 12, 16, 20 or 24, and n is 1 , 2 or 3, y is 1, 2, 3 or 4, L ₁ is absent.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 12, 16, 20 or 24, and n is 2 , y is 1, 2, 3 or 4, and L ₁ does not exist.

In some embodiments, P is a fusion inhibitory polypeptide targeting gp41 shown in SEQ ID NO: 3, and SM is

The residues of L ₁ and L ₂ are absent; or L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 4 Integer between -24, n is 1, 2 or 3, y is 1, 2, 3 or 4, L ₂ is absent.

The residues of L ₁ and L ₂ are absent; or L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 4 , 8, 12, 16, 20 or 24, n is 1, 2 or 3, y is 1, ₂ , 3 or 4, L2 is absent.

The residues of L ₁ and L ₂ are absent; or L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), where m is 4, 8, 12, 16, 20 or 24, n is ₂ , L2 does not exist.

The residues of L ₁ and L ₂ are absent; or L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 4 Integer between -24, n is 1, 2 or 3, y is 1, 2, 3 or 4, L ₁ is absent.

The residues of L ₁ and L ₂ are absent; or L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 4 , 8, 12, 16, 20 or 24, n is 1, 2 or 3, y is 1, 2, 3 or 4, L ₁ is absent.

The residues of L ₁ and L ₂ are absent; or L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), where m is 4, 8, 12, 16, 20 or 24, n is 2, L ₁ does not exist.

In some embodiments, P is a fusion inhibitory polypeptide targeting gp41 set forth in SEQ ID NO: 6 or SEQ ID NO: 13, and SM is

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is an integer between 4 and 24, and n is 1 , 2 or 3, y is 1, 2, 3 or 4, L ₂ is absent.

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 4, 12, 16, 20 or 24, n is 1, 2, or 3, y is 1, ₂ , 3, or 4, and L2 is absent.

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), wherein m is 4, 12, 16, 20 or 24, n is 2, L ₂ does not exist.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is an integer between 4 and 24, and n is 1 , 2 or 3, y is 1, 2, 3 or 4, L ₁ is absent.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 4, 12, 16, 20 or 24, n is 1, 2, or 3, y is 1, 2, 3, or 4, and L ₁ is absent.

or residue, L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), where m is 4, 12, 16, 20 or 24, n is 2, L ₁ does not exist.

In some embodiments, P is a fusion inhibitory polypeptide targeting gp41 shown in SEQ ID NO: 6, and SM is

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), where m is 4, 12, 16, 20 or 24, n is 2, L ₁ does not exist.

In some embodiments, P is a fusion inhibitory polypeptide targeting gp41 shown in SEQ ID NO: 13, and SM is

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), where m is 24, n is 2, and L ₂ is absent.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), where m is 24, n is 2, and L ₁ is absent.

In some embodiments, P is a fusion inhibitory polypeptide targeting gp41 shown in SEQ ID NO: 4, and SM is

In some embodiments, P is a fusion inhibitory polypeptide targeting gp41 shown in SEQ ID NO: 5, and SM is

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is an integer between 6 and 24, and n is 1 , 2 or 3, y is 1, 2, 3 or 4, L ₂ is absent.

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 6, 8, 12, 16, 20 or 24 , n is 1, 2 or 3, y is 1, 2, 3 or 4, and L ₂ does not exist.

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), wherein m is 6, 8, 12, 16, 20 or 24, and n is 2, _L2 does not exist.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is an integer between 6 and 24, and n is 1 , 2 or 3, y is 1, 2, 3 or 4, L ₁ is absent.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 6, 8, 12, 16, 20 or 24 , n is 1, 2 or 3, y is 1, 2, 3 or 4, and L ₁ does not exist.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), wherein m is 6, 8, 12, 16, 20 or 24, and n is 2, _L1 does not exist.

In some embodiments, P is a fusion inhibitory polypeptide targeting gp41 shown in SEQ ID NO: 12, and SM is

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 12 or 24 and n is 1, 2 or 3 , y is 1, ₂ , 3 or 4, L2 does not exist.

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), wherein m is 24, n is 1, 2 or 3, and L ₂ is absent.

The residue of , L ₁ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), wherein m is 12, n is 1, 2 or 3, and L ₂ is absent.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O) or (GSGSG) _y , where m is 12 or 24 and n is 1, 2 or 3 , y is 1, 2, 3 or 4, and L ₁ does not exist.

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), where m is 24, n is 1, 2 or 3, and L ₁ is absent. In some embodiments, P is a fusion inhibitory polypeptide targeting gp41 shown in SEQ ID NO: 12, and SM is

The residue of , L ₂ is -NH-(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(=O), where m is 12, n is 1, 2 or 3, and L ₁ is absent.

In some embodiments, A may represent 1-30, 1-25, 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1 -8, 1-6, 1-5, 1-4 or 1-3 amino acid residues. In some embodiments, A may represent 3 amino acid residues. In some embodiments, A represents 2 amino acid residues. In some embodiments, A may represent 1 amino acid residue.

In some embodiments, each amino acid residue in A can be any amino acid residue. In some embodiments, A may comprise at least one amino acid residue with a reactive group on the side chain. In some embodiments, A may comprise at least one amino acid residue with a reactive group on the side chain selected from amino, carboxyl, amide, alkynyl, or hydroxyl. In some embodiments, A may comprise at least one amino acid residue with a reactive group on the side chain selected from amino or alkynyl. In some embodiments, A may comprise at least one amino acid residue with an amino group on the side chain. In some embodiments, A may comprise at least one lysine residue or a propargylglycine residue in the L- or D-configuration. In some embodiments, A may comprise at least one lysine residue. In some embodiments, A is a lysine residue.

In some embodiments, A may represent 3 amino acid residues comprising at least one amino acid residue with an amino or alkynyl group on the side chain. In some embodiments, A may represent 3 amino acid residues comprising at least one amino acid residue with an amino group on the side chain. In some embodiments, A may represent 2 amino acid residues comprising at least one amino acid residue with an amino or alkynyl group on the side chain. In some embodiments, A may represent 2 amino acid residues comprising at least one amino acid residue with an amino group on the side chain. In some embodiments, A may represent 1 amino acid residue, which is an amino acid residue with an amino or alkynyl group on the side chain. In some embodiments, A may represent 1 amino acid residue, which is an amino acid residue with an amino group on the side chain.

In some embodiments, a may be absent, in which case the amino terminus of the compound of formula (I) is an amino group. In some embodiments, α can be selected from acetyl, maleyl, succinyl, tert-butoxycarbonyl, benzyloxycarbonyl, dansyl or other hydrophobic groups or macromolecular carrier groups, in which case the formula (I) The amino terminus of the compound is the group or the group obtained after the condensation reaction with the amino group. In some embodiments, α can be selected from acetyl, maleyl, succinyl, tert-butoxycarbonyl, benzyloxycarbonyl, dansyl; C10-C30 hydrocarbon groups, including aryl, ester, ether, amine, amide, etc. hydrocarbyl groups, hydrocarbyl groups containing double bonds, polyoxypropylene groups, long-chain perfluoroalkyl groups, polysiloxane groups; or lipid-fatty acid conjugates, polyethylene glycol, carbohydrate-based groups, the In this case, the amino terminal of the compound of formula (I) is the group or the group obtained by condensation reaction with the amino group. In some embodiments, α can be selected from acetyl, maleyl, succinyl, t-butoxycarbonyl, benzyloxycarbonyl, dansyl; or a C10-C30 hydrocarbyl, in which case the amino terminus of the compound of formula (I) That is, the group or the group obtained by the condensation reaction with the amino group. In some embodiments, α can be selected from acetyl, maleyl, succinyl, t-butoxycarbonyl, benzyloxycarbonyl, dansyl; or a C10-C20 hydrocarbyl, in which case the amino terminus of the compound of formula (I) That is, the group or the group obtained by the condensation reaction with the amino group. In some embodiments, α can be selected from acetyl, maleyl, succinyl, t-butoxycarbonyl, benzyloxycarbonyl, dansyl; or C12 hydrocarbyl, in which case the amino terminus of the compound of formula (I) is The above-mentioned group or the group obtained by the condensation reaction with the amino group. In some embodiments, α can be selected from acetyl, maleyl, succinyl, t-butoxycarbonyl, benzyloxycarbonyl, dansyl; or C14 hydrocarbyl, in which case the amino terminus of the compound of formula (I) is The above-mentioned group or the group obtained by the condensation reaction with the amino group. In some embodiments, α can be selected from acetyl, maleyl, succinyl, t-butoxycarbonyl, benzyloxycarbonyl, dansyl; or C16 hydrocarbyl, in which case the amino terminus of the compound of formula (I) is The above-mentioned group or the group obtained by the condensation reaction with the amino group. In some embodiments, α can be selected from acetyl, maleyl, succinyl, tert-butoxycarbonyl, benzyloxycarbonyl, dansyl; or C18 hydrocarbyl, in which case the amino terminus of the compound of formula (I) is The above-mentioned group or the group obtained by the condensation reaction with the amino group. In some embodiments, a may be an acetyl group, in which case the amino terminus of the compound of formula (I) is an acetyl group.

In some embodiments, β may be absent, in which case the carboxy terminus of the compound of formula (I) is the carboxy group. In some embodiments, β can be selected from amino groups or other hydrophobic groups or macromolecular carrier groups, and in this case, the carboxyl terminus of the compound of formula (I) is the group or the product obtained by condensation reaction with the carboxyl group. group. In some embodiments, β can be selected from amino groups; C10-C30 hydrocarbon groups, hydrocarbon groups containing aryl, ester, ether, amine, amide and other groups, hydrocarbon groups containing double bonds, polyoxypropylene groups, long-chain perfluoro Alkyl group, polysiloxane group; or lipid-fatty acid conjugate, polyethylene glycol, carbohydrate group, in this case, the carboxyl terminus of the compound of formula (I) is the group or its combination with the carboxyl group A group obtained after a condensation reaction has occurred. In some embodiments, β can be selected from amino groups; or C10-C30 hydrocarbon groups, in which case the carboxyl terminus of the compound of formula (I) is the group or the group obtained by condensation reaction with the carboxyl group. In some embodiments, β can be selected from amino groups; or C10-C20 hydrocarbon groups, in which case the carboxyl terminus of the compound of formula (I) is the group or the group obtained by condensation reaction with the carboxyl group. In some embodiments, β can be selected from amino group; or C12 hydrocarbon group, in this case, the carboxyl terminus of the compound of formula (I) is the group or the group obtained by condensation reaction with the carboxyl group. In some embodiments, β can be selected from amino group; or C14 hydrocarbon group, in this case, the carboxyl terminus of the compound of formula (I) is the group or the group obtained by condensation reaction with the carboxyl group. In some embodiments, β can be selected from amino group; or C16 hydrocarbon group, in this case, the carboxyl terminus of the compound of formula (I) is the group or the group obtained by condensation reaction with the carboxyl group. In some embodiments, β can be selected from amino group; or C18 hydrocarbon group, in this case, the carboxyl terminus of the compound of formula (I) is the group or the group obtained by condensation reaction with the carboxyl group. In some embodiments, β may be an amino group, in which case the carboxy terminus of the compound of formula (I) is an amide group.

The various embodiments and preferences described above for the compounds of formula (I) of the present disclosure may be combined with each other (as long as they are not inherently inconsistent with each other), and the various embodiments formed by such combinations are considered to be part of this disclosure.

The present disclosure may also provide a composition comprising a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.

The present disclosure may also provide the use of a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a composition according to the present disclosure, in the manufacture of a medicament for the prevention or treatment of AIDS.

The various embodiments and preferences described above for the compounds of the present disclosure apply equally to the compositions and uses of the present disclosure, and these embodiments and preferences may also be combined with each other (as long as they are not inherently inconsistent with each other), Various embodiments formed by this combination are considered to be part of the disclosure of the present application.

The technical solutions of the present disclosure will be more clearly and clearly described below with reference to the embodiments by way of illustration. It should be understood that these examples are for illustrative purposes only and are in no way intended to limit the scope of protection of the present disclosure. The scope of protection of the present disclosure is limited only by the claims.

Example

Materials and methods

Unless otherwise stated, the reagents and instruments used were conventional products that are commercially available. Unless otherwise stated, experiments were performed under conventional conditions or as suggested by the manufacturer.

The solid phase synthesis carrier Rink amide resin used is the product of Tianjin Nankai Synthetic Co., Ltd.; HBTU, HOBT, DIEA and Fmoc protected natural amino acids or D-type unnatural amino acids are products of Shanghai Jier Biochemical Company and Chengdu Chengnuo New Technology Co., Ltd. ; N-methylpyrrolidone (NMP) is a product of ACROS company; Trifluoroacetic acid (TFA) is a product of Beijing Bomeijie Technology Co., Ltd.; DMF and DCM are products of South Korea's Samsung company; chromatographically pure acetonitrile is a product of Fisher company; other reagents such as Unless otherwise stated, they are all domestic analytically pure products.

CEMx174 5.25M7 cells were provided by the National Institutes of Health AIDS Research and Reference Reagent Program (NIH AIDS RRRP); laboratory-adapted strains BaL and IIIB, T20-resistant strains, and HIV clinical isolates were provided by the NIH AIDS RRRP in the United States. RPMI-1640 medium, DMEM cell culture medium, newborn bovine serum, fetal bovine serum and trypsin/EDTA digestion solution, penicillin and streptomycin were purchased from Gibco, USA.

Example 1: Synthesis and Activity Testing of Compounds Containing C34 Polypeptides

Example 1-1: Synthesis of Compound 1-1

1-1.1 Synthesis of TAK compounds

TAK-220 was synthesized as described in J. Med. Chem. 2006, 49, 2784-2793, and TAK was synthesized.

1-1.2 Synthesis of Polypeptide Resin

Polypeptides were synthesized by standard Fmoc solid-phase synthesis (Solid Phase Peptide Synthesis, SPPS). The reagents used in the synthesis process, such as DMF, methanol, DCM, piperidine and NMP, etc., were all dried before use. Rink amide resin was selected as the solid phase carrier, and the resin loading was 0.44 mmol/g. The synthetic steps of the polypeptide resin are basically shown in Figure 2.

(1) Swelling of resin: Weigh 0.25g of Rink amide resin into a 50mL centrifuge tube, add 10mL of DCM, and swell for 15min.

(2) Removal of Fmoc protecting group on resin: add a deprotection reagent to the swollen resin, and the deprotection reagent is 20% piperidine/DMF solution (v/v). The removal of Fmoc was divided into two times. The first time was to add 5 mL of deprotection reagent and continue to stir for 5 min, and then drain it. For the second time, 5 mL of deprotection reagent was added to continue to stir for 25 min and then drained. Then wash twice with 5mL DMF, 5mL methanol, 5mL dichloromethane successively, then take a small amount of deprotected resin for detection, and detect at 110 ° C for 3min. Remove the detection tube from the heater and observe the phenomenon. If the resin appears blue, the deprotection is complete, and the next step of amino acid condensation can be performed. Otherwise, the adjustment procedure is repeated and step (2) is repeated until the resin appears blue.

(3) Condensation reaction of amino acids: add the deprotected resin to a microwave peptide synthesizer (purchased from CEM), and add 3 mL of amino acid solution (0.1 M) and 5 mL of condensation reagent (0.3 M HBTU/0.3 M HOBt/DMF) and 5 mL of activated base solution (0.6M DIEA/NMP), stirring at room temperature. After the reaction was completed, the peptide resin was washed twice with 5 mL of DMF, 5 mL of methanol, and 5 mL of dichloromethane, respectively, and then a small amount of peptide resin was taken for detection at 110 °C for 3 min. Remove the detection tube from the heater and observe the phenomenon. If the resin appears blue, it means that the amino acid condensation is not complete, repeat step (3) until the reaction is complete and the resin appears yellow. If the resin is yellow, repeat steps (2) and (3), and continue to condense the next amino acid until the synthesis of the polypeptide is complete.

(4) Acetylation end-capping: After the synthesis of the polypeptide, the Fmoc protecting group was removed, and after washing, 2 mL of DIEA and 2 mL of acetic anhydride were added, and 4 mL of DMF was added simultaneously, and the reaction was repeated for 30 min. After the reaction was completed, the polypeptide resin was washed and a small amount was taken for detection, which was detected at 110 °C for 3 min. Remove the detection tube from the heater and observe the phenomenon. The resin is yellow, indicating that the capping is complete. Wash and drain. 2.05g of polypeptide resin was obtained.

1-1.3 Synthesis of compound 1-1

To the polypeptide resin obtained in 1.2, 5 mL of 2% hydrazine hydrate/DMF solution was added, stirred at room temperature for 3 min, drained, and repeated five times. Then, it was washed five times with DMF, DCM and methanol, respectively. At this time, the Dde group of the lysine of the Dde-protected side chain in the polypeptide resin is removed, and the amino group of the side chain is exposed. Subsequently, the PEG12 flexible linker (-NH-(CH ₂ CH ₂ O) ₁₂ -(CH ₂ ) ₂ -C(=O)-, the same below) and TAK were condensed in turn by the same polypeptide synthesis method to obtain a conjugated Polypeptide resin.

Preparation of lysate: the composition of the lysate is trifluoroacetic acid: anisole: ethanedithiol: m-cresol: water = 82.5:5:2.5:5:5 (volume percentage), which needs to be cooled in an ice bath for 30min or Store in the refrigerator in advance for use.

Weigh 2.05g of the conjugated polypeptide resin, put it into a 250ml eggplant-shaped bottle, add 20.5ml of lysis solution in an ice bath, stir electromagnetically, the resin turns orange-red, react under ice bath conditions for 30 minutes, then remove the ice bath, and at room temperature The stirring reaction was continued for 90 min. Then, 200 ml of cold ether was added under vigorous stirring, and a white precipitate was precipitated, and the stirring was continued for 30 min; Subsequently, 50 mL of double distilled water and 5 mL of acetonitrile were added to fully dissolve the solid, suction filtration, and the filtrate was freeze-dried to obtain 1.03 g of crude compound 1-1.

The obtained crude compound 1-1 was purified by high pressure chromatography, wherein the chromatography column was a C8 column, and the eluent was acetonitrile, water and a small amount of trifluoroacetic acid. The specific operation steps are as follows: Weigh 1.00 g of crude compound 1-1, add 20 mL of water and 5 mL of acetonitrile to dissolve the solid, centrifuge for 10 min (3000 rpm), and take the supernatant for loading. The column was pre-equilibrated with 200 mL of 15% acetonitrile/water/0.1% trifluoroacetic acid solution. After loading the sample, continue to rinse with 200 mL of 15% acetonitrile/water/0.1% trifluoroacetic acid solution, and detect the components of the eluent by high performance liquid phase. According to the liquid phase detection results, the acetonitrile content was gradually increased until the main peak of the purified compound 1-1 was eluted. The eluates were combined, most of the solvent was removed by rotary evaporation, and the purified compound 1-1 was obtained by lyophilization. The purity detected by HPLC was 98.0%. The molecular weight of compound 1-1 was determined using MALDI-TOF-MS, and the result is shown in Figure 3, wherein the calculated molecular weight is 5553.63.

The structural formula of compound 1-1 is shown below.

For simplicity, the structure of compound 1-1 is roughly represented by "C34 polypeptide-K (PEG12-TAK)" in Table 1 below.

Example 1-2: Synthesis of Compound 1-2

Compound 1-2 was synthesized by the same method as in Example 1, wherein the difference between compound 1-2 and compound 1-1 was that PEG6 type flexible linker (-NH-(CH ₂ CH ₂ O) ₆ -(CH ₂ ) was used ) ₂ -C(=O)-, the same below) replaces the PEG12 flexible linking arm. For simplicity, the structure of compound 1-2 is roughly represented by "C34 polypeptide-K (PEG6-TAK)" in Table 1 below.

Example 1-3: Synthesis of Compound 1-3

Compound 1-3 was synthesized by the same method as in Example 1, wherein the difference between compound 1-3 and compound 1-1 was that the position of the flexible linker was different, and the side chain of the flexible linker and lysine in compound 1-1 was different. It is directly connected to TAK, and the flexible linker in compound 1-3 is located between the lysine and C34 polypeptide (SEQ ID NO: 1) connected with TAK in the side chain, that is, the carboxyl group of the linker is connected with the side chain of TAK. The α-amino group of lysine is linked; while the amino group of the linker is linked to the carboxy terminus of the C34 polypeptide. For simplicity, the structures of compounds 1-3 are roughly represented in Table 1 below as "C34 polypeptide-PEG12-K(TAK)".

Examples 1-4: Synthesis of Compounds 1-15

Compound 1-15 was synthesized by a method similar to that in Example 1, wherein the difference between compound 1-15 and compound 1-1 was that 2 tandem GSGSGs (ie (GSGSG) ₂ , abbreviated as (Z) ₂ ) were used instead of PEG12 Type flexible connecting arm. For simplicity, the structures of compounds 1-15 are roughly represented in Table 1 below as "C34 polypeptide K[(Z) ₂ -TAK]".

Examples 1-5: Synthesis of Compounds 1-16

Compound 1-16 was synthesized by a method similar to that in Example 1, wherein the difference between compound 1-16 and compound 1-1 was that 3 GSGSGs in series (ie (GSGSG) ₃ , abbreviated as (Z) ₃ ) were used instead of PEG12 Type flexible connecting arm. For simplicity, the structures of compounds 1-16 are roughly represented in Table 1 below as "C34 polypeptide K[(Z) ₃ -TAK]".

Examples 1-6: Synthesis of Compounds 1-17

Compound 1-17 was synthesized by a method similar to that in Example 1, wherein the difference between compound 1-17 and compound 1-1 was that 4 tandem GSGSGs (ie (GSGSG) ₄ , abbreviated as (Z) ₄ ) were used instead of PEG12 Type flexible connecting arm. For simplicity, the structures of compounds 1-17 are roughly represented in Table 1 below as "C34 polypeptide K[(Z) ₄ -TAK]".

Comparative Example 1-1: Synthesis of Compound 1-4

Compound 1-4 was synthesized by the same method as Example 1, wherein the difference between compound 1-4 and compound 1-1 was that no flexible linking arm was included. For simplicity, the structures of compounds 1-4 are roughly represented in Table 1 below by "C34 polypeptide-K (TAK)".

Comparative Example 1-2: Synthesis of Compounds 1-5

Compound 1-5 was synthesized by the same method as in Example 1, wherein the difference between compound 1-5 and compound 1-1 was: the use of a PEG4 type flexible linking arm (-NH-(CH ₂ CH ₂ O) ₄ -(CH ₂ ) ₂ -C(=O)-, the same below) replaces the PEG12 flexible linking arm. For simplicity, the structures of compounds 1-5 are roughly represented in Table 1 below as "C34 polypeptide-K (PEG4-TAK)".

Comparative Example 1-3: Synthesis of Compounds 1-6

Compound 1-6 was synthesized by the same method as in Example 1, wherein the difference between compound 1-6 and compound 1-1 was: the use of PEG24 type flexible linking arm (-NH-(CH ₂ CH ₂ O) ₂₄ -(CH ₂ ) ₂ -C(=O)-, the same below) replaces the PEG12 flexible linking arm. For simplicity, the structures of Compounds 1-6 are roughly represented by "C34 polypeptide-K (PEG24-TAK)" in Table 1 below.

Comparative Examples 1-4: Synthesis of Compounds 1-7

Compound 1-7 was synthesized by the same method as in Example 1, wherein the difference between compound 1-7 and compound 1-1 was that β-alanine was used instead of PEG12-type flexible linking arm. For simplicity, the structures of compounds 1-7 are roughly represented in Table 1 below as "C34 polypeptide-K (βAla-TAK)".

Comparative Examples 1-5: Synthesis of Compounds 1-8

Compound 1-8 was synthesized by the same method as in Example 1, wherein the difference between compound 1-8 and compound 1-1 was that 6-aminocaproic acid was used instead of PEG12 type flexible linking arm. For simplicity, the structures of compounds 1-8 are roughly represented in Table 1 below as "C34 polypeptide-K (Aca-TAK)".

Comparative Examples 1-6: Synthesis of Compounds 1-9

Compound 1-9 was synthesized by the same method as in Example 1, wherein the difference between compound 1-9 and compound 1-1 is that the fusion inhibitory polypeptide targeting gp41 is not a C34 polypeptide, but a polypeptide shown in SEQ ID NO: 9 . For simplicity, the structures of compounds 1-9 are roughly represented by "polypeptide-K (PEG12-TAK) shown in SEQ ID NO: 9" in Table 1 below.

Comparative Examples 1-7: Synthesis of Compounds 1-10

Compound 1-10 was synthesized by the same method as in Example 1, wherein the difference between compound 1-10 and compound 1-1 was that the fusion inhibitory polypeptide targeting gp41 was not a C34 polypeptide, but a polypeptide shown in SEQ ID NO: 10 . For simplicity, the structures of compounds 1-10 are roughly represented by "polypeptide-K (PEG12-TAK) shown in SEQ ID NO: 10" in Table 1 below.

Comparative Examples 1-8: Synthesis of Compounds 1-11

Compound 1-11 was synthesized by the same method as in Example 2, wherein the difference between compound 1-11 and compound 1-2 was that the fusion inhibitory polypeptide targeting gp41 was located at the carboxyl terminus of lysine instead of the amino terminus. For simplicity, the structures of compounds 1-11 are roughly represented in Table 1 below as "(TAK-PEG6)K-C34 polypeptide".

Comparative Examples 1-9: Synthesis of Compounds 1-12

Compound 1-12 was synthesized by the same method as in Comparative Example 8, wherein the difference between compound 1-12 and compound 1-11 was that a PEG3 type flexible linker (-NH-(CH ₂ CH ₂ O) ₃ -(CH ₂ ) was used. ) ₂ -C(=O)-, the same below) replaces the PEG12 flexible linking arm. For simplicity, the structures of compounds 1-12 are roughly represented in Table 1 below as "(TAK-PEG3)K-C34 polypeptide".

Comparative Examples 1-10: Synthesis of Compounds 1-13

Compound 1-13 was synthesized by the same method as in Example 1. The amino acid sequence of compound 1-13 is shown in SEQ ID NO: 1 (C34 polypeptide), which is acetylated at the amino terminus and amidated at the carboxyl terminus. For simplicity, the structures of compounds 1-13 are roughly represented in Table 1 below as "C34 polypeptide".

Comparative Examples 1-11: Synthesis of Compounds 1-14

Compound 1-14 was synthesized by a method similar to that in Example 1, wherein the difference between compound 1-14 and compound 1-1 was that a PEG8 type flexible linker (-NH-(CH ₂ CH ₂ O) ₈ -(CH ₂ ) was used ) ₂ -C(=O)-, the same below) replaces the PEG12 flexible linking arm. For simplicity, the structures of compounds 1-14 are roughly represented in Table 1 below as "C34 polypeptide-K (PEG8-TAK)".

Comparative Examples 1-12: Synthesis of Compounds 1-18

Compound 1-18 was synthesized by a method similar to that in Example 1, wherein the difference between compound 1-18 and compound 1-1 was that the Dde group of the lysine of the Dde-protected side chain in the polypeptide resin was removed, and the amino group of the side chain was exposed. After that, only the PEG12-type flexible linker was condensed with it, and then no longer condensed with TAK, and the C-terminus of the PEG12-type flexible linker was modified with an acetyl group. For simplicity, the structures of compounds 1-18 are roughly represented in Table 1 below as "C34 polypeptide K(PEG12-Ac)".

Comparative Examples 1-13: Synthesis of Compounds 1-19

Compound 1-19 was synthesized by a method similar to Example 1, wherein the amino acid sequence of compound 1-19 is shown in SEQ ID NO: 11, which is acetylated at the amino terminus and amidated at the carboxyl terminus.

Examples 1-7: Anti-HIV activity test

1. Dilute the compound to be tested and add it to a 96-well cell culture plate, 50 μL/well;

2. Incubate 100 times the HIV strain with 50% tissue infection concentration TCID ₅₀ , 50 μL/well, and the samples to be tested at each concentration for 30 min at 37°C;

3. Add 1×10 ⁵ /mL, 100 μL/well of CEMx174 5.25 M7 cells to the above culture plate, and culture at 37°C and 5% CO ₂ overnight;

4. The next day, 150 μL/well supernatant was discarded, and fresh RPMI-1640 medium containing 10% FBS was added;

5. On the 4th day after infection, the cytopathic effect of CPE was observed, 100 μL/well culture supernatant was mixed with an equal amount of 5% TritonX-100, and after virus lysis, the content of p24 antigen in the supernatant was determined by ELISA method.

6. Calculate _EC50 values using Calcusyn software. The results are shown in Tables 1-3 below.

Table 1: EC ₅₀ of test compounds in CEMx174 5.25M7 cells infected with HIV strains Bal and IIIB, respectively

The results show:

(1) Compounds 1-1, 1-2 and 1-3 and 1-14, 1-15, 1-16 and 1-17 all effectively inhibited R5 type HIV strain Bal and X4 type HIV strain IIIB, which Anti-HIV activity at low nanomolar levels, significantly better than C34 polypeptide alone, Compounds 1-18 alone, TAK-220 alone, physical mixtures of TAK-220 and C34 polypeptides, and TAK-220 and Compound 1- A physical mixture of 18. It can be seen that after covalently conjugating a fusion inhibitory polypeptide targeting gp41 (eg, C34 polypeptide) with a small molecule inhibitor of CCR5 (eg, TAK220), the resulting compounds of the present disclosure are more efficient than those targeting gp41 alone. of fusion inhibitory polypeptides, covalent conjugates of fusion inhibitory polypeptides targeting gp41 with a PEG12-type flexible linker (via the side chain of lysine), small molecule inhibitors of CCR5 alone, fusion inhibitory polypeptides targeting gp41, and Physical mixtures of CCR5 small molecule inhibitors, covalent conjugates of gp41-targeting fusion inhibitory polypeptides with PEG12-type flexible linkers, and physical mixtures of CCR5 small-molecule inhibitors exhibited significantly enhanced anti-HIV activity, demonstrating that targeting gp41 The fusion inhibitory polypeptide covalently linked with the CCR5 small molecule inhibitor indeed played a strong synergistic effect. In addition, either a PEG-type flexible linker (eg, a PEG6-type flexible linker, a PEG8-type flexible linker, a PEG12-type flexible linker) or a flexible peptide (eg, GSGSG) can be beneficial as linkers.

(2) The anti-HIV activities of compounds 1-1, 1-2 and 1-3 and 1-14, 1-15, 1-16 and 1-17 are far superior to those of compounds 1-4, 1-5 and 1- The anti-HIV activities of 6, 1-7, and 1-8, and the anti-HIV activities of compounds 1-1, 1-2, and 1-3, and 1-14, 1-15, 1-16, and 1-17, respectively, have each other varying degrees of difference. This indicates that the presence, length and flexibility of the linker between the gp41-targeting fusion inhibitory polypeptide and the CCR5 small molecule inhibitor have significant effects on the anti-HIV activity of the conjugated polypeptide.

(3) Compounds 1-1 and 1-3 both showed excellent anti-HIV activity. This indicates that the flexible linker is either directly attached to the side chain of lysine (corresponding to A in formula (I)) and TAK (corresponding to SM in formula (I)), or to C34 (corresponding to formula (I) The fusion inhibitory polypeptide targeting gp41 in I) and the amino terminal residue of lysine (corresponding to A in formula (I)) are directly connected, and the obtained compounds of the present disclosure can achieve strong synergistic effect.

(4) The anti-HIV activity of compound 1-2 is far superior to that of compound 1-11. This indicates that the CCR5 small molecule antagonist at the carboxyl terminus of the gp41-targeting fusion inhibitory polypeptide achieves significantly enhanced anti-HIV activity compared to when it is at the amino terminus of the gp41-targeting fusion inhibitory polypeptide.

(5) The anti-HIV activity of compound 1-1 is far superior to that of compounds 1-9 and 1-10. This shows that a particularly beneficial technical effect is achieved when the fusion inhibitory polypeptide targeting gp41 in the compounds of the present disclosure is selected as the C34 polypeptide.

(6) The anti-HIV activities of compounds 1-1, 1-2 and 1-3 and 1-14, 1-15, 1-16 and 1-17 were significantly better than those of compound 1-19, indicating that the compounds of the present disclosure are relatively The FDA-approved HIV fusion inhibitor T20 achieved even better results.

Table 2: EC ₅₀ of test compounds in cells infected with HIV strains 91US_4, 92UG024, 93/BR/020, respectively

The results showed that compound 1-1 effectively inhibited the activity of R5 HIV strain 91US_4, X4 HIV strain 92UG024 and X4/R5 HIV strain 93/BR/020, and its effect was significantly better than that of single compound 1-13 , TAK-220 alone, and a physical mixture of the two. This indicates that the compounds of the present disclosure can effectively inhibit various HIV clinical strains. In addition, it can be seen from the above table that the CCR5 small molecule antagonist TAK-220 has no inhibitory activity against X4 type or X4/R5 type HIV, while the compounds of the present disclosure have efficient inhibitory activity against the above two types of viruses. Thus, it is proved that the present invention solves the defect that CCR5 small molecule antagonists are only effective against R5 virus by co-conjugating the CCR5 small molecule antagonists with the fusion inhibitory polypeptide targeting gp41 in a specific manner.

Table 3: _EC50 of test compounds in cells infected with HIV strains V38E/N42S, N42T/N43K, V38A/N42T, respectively

The results showed that compound 1-1 effectively inhibited the activity of drug-resistant strains V38E/N42S, N42T/N43K and V38A/N42T of the listed drug T20, and its effect was significantly better than that of single compound 1-13 and T20. This shows that the compounds of the present disclosure can effectively inhibit multiple drug-resistant strains of the marketed drug T20, and effectively solve the drug resistance problem of HIV fusion inhibitors.

Example 2: Synthesis of Compounds Containing FB006 Polypeptides and Testing of Their Activity

The following compounds were synthesized in a manner similar to that described in Example 1 .

Example 2-1: Synthesis of Compound 2-1

The difference between compound 2-1 and compound 1-1 is that FB006 polypeptide is used instead of C34 polypeptide. For simplicity, the structure of compound 2-1 is roughly represented by "FB006 polypeptide-K (PEG12-TAK)" in Table 4 below.

Example 2-2: Synthesis of Compound 2-3

The difference between compound 2-3 and compound 2-1 is that PEG16 type flexible linking arm (-NH-(CH ₂ CH ₂ O) ₁₆ -(CH ₂ ) ₂ -C(=O)-, the same below) is used instead of PEG12 Type flexible connecting arm. For simplicity, the structure of compound 2-3 is roughly represented in Table 4 below as "FB006 polypeptide-K (PEG16-TAK)".

Example 2-3: Synthesis of Compound 2-4

The difference between compound 2-4 and compound 2-1 is that PEG20 type flexible linking arm (-NH-(CH ₂ CH ₂ O) ₂₀ -(CH ₂ ) ₂ -C(=O)-, the same below) is used instead of PEG12 Type flexible connecting arm. For simplicity, the structure of compound 2-4 is roughly represented by "FB006 polypeptide-K (PEG20-TAK)" in Table 4 below.

Example 2-4: Synthesis of Compound 2-5

The difference between compound 2-5 and compound 2-1 is that a PEG24-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 2-5 are roughly represented in Table 4 below as "FB006 polypeptide-K (PEG24-TAK)".

Example 2-5: Synthesis of Compound 2-6

The difference between compound 2-6 and compound 2-1 is that GSGSG (abbreviated as Z) is used instead of the PEG12-type flexible linking arm. For simplicity, the structures of compounds 2-6 are roughly represented in Table 4 below as "FB006 polypeptide-K (Z-TAK)".

Example 2-6: Synthesis of Compound 2-7

The difference between compound 2-7 and compound 2-1 is that two tandem GSGSGs (ie (GSGSG) ₂ , abbreviated as (Z) ₂ ) are used instead of PEG12-type flexible linkers. For simplicity, the structures of compounds 2-7 are roughly represented in Table 4 below as "FB006 polypeptide K[(Z) ₂ -TAK]".

Example 2-7: Synthesis of Compound 2-8

The difference between compound 2-8 and compound 2-1 is that three tandem GSGSGs (ie (GSGSG) ₃ , abbreviated as (Z) ₃ ) are used instead of PEG12-type flexible linkers. For simplicity, the structures of compounds 2-8 are roughly represented in Table 4 below as "FB006 polypeptide K[(Z) ₃ -TAK]".

Example 2-8: Synthesis of Compound 2-9

Compound 2-9 differs from compound 2-1 in that 4 tandem GSGSGs (ie (GSGSG) ₄ , abbreviated as (Z) ₄ ) are used instead of PEG12-type flexible linkers. For simplicity, the structures of compounds 2-9 are roughly represented in Table 4 below as "FB006 polypeptide K[(Z) ₄ -TAK]".

Comparative Example 2-1: Synthesis of Compound 2-2

The difference between compound 2-2 and compound 2-1 is that PEG8 type flexible linking arm (-NH-(CH ₂ CH ₂ O) ₈ -(CH ₂ ) ₂ -C(=O)-, the same below) is used instead of PEG12 Type flexible connecting arm. For simplicity, the structure of compound 2-2 is roughly represented by "FB006 polypeptide-K (PEG8-TAK)" in Table 4 below.

Comparative Example 2-2: Synthesis of Compound 2-10

The amino acid sequence of compound 2-10 is shown in SEQ ID NO: 7, which is acetylated at the amino terminus and amidated at the carboxy terminus. For simplicity, the structures of compounds 2-10 are roughly represented in Table 4 below as "FB006 polypeptide".

Example 2-9: Anti-HIV activity test

HIV activity tests (triplicates, the same below) were performed as described in Examples 1-7, and the results are shown in Table 4.

Table 4: _EC50 of test compounds in CEMx174 5.25M7 cells infected with HIV strain Bal

The results show:

(1) Compounds 2-1, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, and 2-9 all effectively inhibited the R5 HIV strain Bal, which has low sodium Molar level of anti-HIV activity significantly better than TAK-220 alone, FB006 polypeptide alone, a physical mixture of TAK-220 and FB006 polypeptide, of which 2-5, 2-6, 2-7, 2-8 exhibited The anti-HIV activity is particularly prominent. It can be seen that after covalently conjugating a fusion inhibitory polypeptide targeting gp41 (eg, FB006 polypeptide) to a small molecule inhibitor of CCR5 (eg, TAK-220), the resulting compounds of the present disclosure are better than the individual targets The anti-HIV activity of the physical mixture of the fusion inhibitory polypeptide to gp41, the CCR5 small molecule inhibitor alone, the fusion inhibitory polypeptide targeting gp41, and the small molecule inhibitor of CCR5 was significantly improved, demonstrating that the fusion inhibitory polypeptide targeting gp41 with CCR5 The covalent attachment of the small molecule inhibitor indeed played a strong synergistic effect. In addition, either a PEG-type flexible linker (eg, a PEG12-type flexible linker, a PEG16-type flexible linker,) or a flexible peptide (eg, GSGSG) can be beneficial as linkers.

(2) The anti-HIV activity of compounds 2-1, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9 is far superior to that of compound 2-2 , and the respective anti-HIV activities of compounds 2-1, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, and 2-9 were different from each other to different degrees. This indicates that the length and type of the linker between the fusion inhibitory polypeptide targeting gp41 and the CCR5 small molecule inhibitor have a significant effect on the anti-HIV activity of the conjugated polypeptide.

Example 3: Synthesis and Activity Testing of Compounds Comprising AP3 Polypeptides

Example 3-1: Synthesis of Compound 3-1

The difference between compound 3-1 and compound 1-1 is that AP3 polypeptide is used instead of C34 polypeptide. For simplicity, the structure of compound 3-1 is roughly represented by "AP3 polypeptide-K (PEG12-TAK)" in Table 5 below.

Example 3-2: Synthesis of Compound 3-2

The difference between compound 3-2 and compound 3-1 is that the PEG12-type flexible linking arm is removed. For simplicity, the structure of compound 3-2 is roughly represented by "AP3 polypeptide-K (TAK)" in Table 5 below.

Example 3-3: Synthesis of Compound 3-3

The difference between compound 3-3 and compound 3-1 is that a PEG4-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structure of compound 3-3 is roughly represented in Table 5 below by "AP3 polypeptide-K (PEG4-TAK)".

Example 3-4: Synthesis of Compound 3-4

The difference between compound 3-4 and compound 3-1 is that a PEG8-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of Compounds 3-4 are roughly represented by "AP3 polypeptide-K (PEG8-TAK)" in Table 5 below.

Example 3-5: Synthesis of Compound 3-5

The difference between compound 3-5 and compound 3-1 is that a PEG16-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 3-5 are roughly represented by "AP3 polypeptide-K (PEG16-TAK)" in Table 5 below.

Example 3-6: Synthesis of Compound 3-6

The difference between compound 3-6 and compound 3-1 is that a PEG20 type flexible linker is used instead of a PEG12 type flexible linker. For simplicity, the structures of compounds 3-6 are roughly represented in Table 5 below by "AP3 polypeptide-K (PEG20-TAK)".

Example 3-7: Synthesis of compound 3-7

The difference between compound 3-7 and compound 3-1 is that a PEG24-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 3-7 are roughly represented in Table 5 below by "AP3 polypeptide-K (PEG24-TAK)".

Comparative Example 3-1: Synthesis of Compound 3-8

The difference between compound 3-8 and compound 3-1 is that the AP3 polypeptide is replaced by the polypeptide shown in SEQ ID NO: 10. For simplicity, the structures of compounds 3-8 are represented roughly in "SEQ ID NO: 10-K (PEG12-TAK)" in Table 5 below.

Comparative Example 3-2: Synthesis of Compound 3-9

The amino acid sequence of compounds 3-9 is shown in SEQ ID NO: 3, which is acetylated at the amino terminus and amidated at the carboxy terminus. For simplicity, the structures of compounds 3-9 are roughly represented in Table 5 below as "AP3 polypeptide".

Example 3-8: Anti-HIV activity test

HIV activity tests were performed as described in Examples 1-7 and the results are shown in Table 5.

Table 5: _EC50 of test compounds in CEMx174 5.25M7 cells infected with HIV strain Bal

The results show:

(1) Compounds 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, and 3-7 all effectively inhibited the R5 HIV strain Bal, which has a low nanomolar level of resistance to HIV activity, the effect is significantly better than TAK-220 alone, AP3 polypeptide alone, physical mixture of TAK-220 and AP3 polypeptide, among which compounds 3-2, 3-3, 3-4, 3-6 exhibited anti-HIV activity The activity was particularly outstanding, and compounds 3-3 exhibited better anti-HIV activity. It can be seen that after covalently conjugating a fusion inhibitory polypeptide targeting gp41 (eg, AP3 polypeptide) to a small molecule inhibitor of CCR5 (eg, TAK-220), the resulting compounds of the present disclosure are more efficient than the target alone The anti-HIV activity of the physical mixture of the fusion inhibitory polypeptide to gp41, the CCR5 small molecule inhibitor alone, the fusion inhibitory polypeptide targeting gp41, and the small molecule inhibitor of CCR5 was significantly improved, demonstrating that the fusion inhibitory polypeptide targeting gp41 with CCR5 The covalent attachment of the small molecule inhibitor indeed played a strong synergistic effect.

(2) The anti-HIV activity of compound 3-1 is far superior to that of compound 3-8. This shows that a particularly beneficial technical effect is achieved when the fusion inhibitory polypeptide targeting gp41 in the compounds of the present disclosure is selected as the AP3 polypeptide.

(3) The anti-HIV activities of compounds 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, and 3-7 are different from each other to different degrees, which indicates that the gp41-targeting The presence or absence and length of the linker between the fusion inhibitory polypeptide and the CCR5 small molecule inhibitor had a significant effect on the anti-HIV activity of the conjugated polypeptide.

Example 4: Synthesis and Activity Testing of Compounds Containing P52 Polypeptides

Example 4-1: Synthesis of Compound 4-1

The difference between compound 4-1 and compound 1-1 is that P52 polypeptide is used instead of C34 polypeptide. For simplicity, the structure of compound 4-1 is roughly represented by "P52 polypeptide-K (PEG12-TAK)" in Table 6 below.

Example 4-2: Synthesis of Compound 4-3

The difference between compound 4-3 and compound 4-1 is that a PEG4-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structure of compound 4-3 is roughly represented by "P52 polypeptide-K (PEG4-TAK)" in Table 6 below.

Example 4-3: Synthesis of Compound 4-5

The difference between compound 4-5 and compound 4-1 is that a PEG16-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 4-5 are roughly represented by "P52 polypeptide-K (PEG16-TAK)" in Table 6 below.

Example 4-4: Synthesis of Compound 4-6

The difference between compound 4-6 and compound 4-1 is that a PEG20 type flexible linker is used instead of a PEG12 type flexible linker. For simplicity, the structures of compounds 4-6 are roughly represented in Table 6 below as "P52 polypeptide-K (PEG20-TAK)".

Example 4-5: Synthesis of compound 4-7

The difference between compound 4-7 and compound 4-1 is that a PEG24-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 4-7 are roughly represented by "P52 polypeptide-K (PEG24-TAK)" in Table 6 below.

Comparative Example 4-1: Synthesis of Compound 4-2

The difference between compound 4-2 and compound 4-1 is that the PEG12-type flexible linking arm is removed. For simplicity, the structure of compound 4-2 is roughly represented by "P52 polypeptide-K (TAK)" in Table 6 below.

Comparative Example 4-2: Synthesis of Compound 4-4

The difference between compound 4-4 and compound 4-1 is that a PEG8-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structure of compound 4-4 is roughly represented by "P52 polypeptide-K (PEG8-TAK)" in Table 6 below.

Comparative Example 4-3: Synthesis of Compound 4-8

The amino acid sequences of compounds 4-8 are shown in SEQ ID NO: 6, which are acetylated at the amino terminus and amidated at the carboxy terminus. For simplicity, the structures of compounds 4-8 are roughly represented in Table 6 below as "P52 polypeptide".

Comparative Example 4-4: Synthesis of Compound 4-9

The difference between compound 4-9 and compound 4-7 is that the polypeptide shown in SEQ ID NO: 13 is used instead of the P52 polypeptide. For simplicity, the structures of compounds 4-9 are represented roughly in "SEQ ID NO: 13-K (PEG24-TAK)" in Table 6 below.

Comparative Example 4-5: Synthesis of Compound 4-10

The difference between compound 4-10 and compound 4-9 is that the position of the PEG24-type flexible linker is different. The PEG24-type flexible linker in compound 4-9 is directly connected to the side chain of lysine and TAK, while the The PEG24-type flexible linker is located between the lysine with TAK attached to the side chain and the polypeptide shown in SEQ ID NO: 13, that is, the carboxyl group of the PEG24-type flexible linker and the α of the lysine with TAK attached to the side chain. The amino group is connected; meanwhile, the amino group of the PEG24-type flexible connecting arm is connected with the carboxyl terminus of the polypeptide shown in SEQ ID NO: 13. For simplicity, the structures of compounds 4-10 are roughly represented in Table 6 below as "SEQ ID NO: 13-PEG24-K(TAK)".

Comparative Example 4-6: Synthesis of Compound 4-11

Compound 4-11 differs from compound 4-10 in that TAKW is used instead of TAK. The structural formula of TAKW is as follows:

The structural formula of compound 4-11 is shown below.

For simplicity, the structures of compounds 4-11 are roughly represented in Table 6 below as "SEQ ID NO: 13-PEG24-K(TAKW)".

Comparative Example 4-7: Synthesis of Compound 4-12

The difference between compound 4-12 and compound 4-10 is that TAK is replaced by B07. The structural formula of B07 is as follows:

The structural formula of compound 4-12 is shown below.

For simplicity, the structures of compounds 4-12 are roughly represented in Table 6 below as "SEQ ID NO: 13-PEG24-K(B07)".

Comparative Example 4-8: Synthesis of Compound 4-13

The difference between compound 4-13 and compound 4-10 is that TAK is replaced by LJC. The structural formula of LJC is as follows:

The structural formula of compound 4-13 is shown below.

For simplicity, the structures of compounds 4-13 are roughly represented in Table 6 below as "SEQ ID NO: 13-PEG24-K(LJC)".

Example 4-6: Anti-HIV activity test

HIV activity tests were performed as described in Examples 1-7 and the results are shown in Table 6.

Table 6: _EC50 of test compounds in CEMx174 5.25M7 cells infected with HIV strain Bal

The results show:

(1) Compounds 4-1, 4-5, 4-6, and 4-7 all effectively inhibited the R5 HIV strain Bal, which has a low nanomolar level of anti-HIV activity, and the effect is significantly better than that of TAK- 220. A separate P52 polypeptide, a physical mixture of TAK-220 and a P52 polypeptide, wherein compounds 4-1 and 4-7 exhibit particularly outstanding anti-HIV activity, and compound 4-7 exhibits more excellent anti-HIV activity. It can be seen that after covalently conjugating a fusion inhibitory polypeptide targeting gp41 (eg, a P52 polypeptide) to a small molecule inhibitor of CCR5 (eg, TAK-220), the resulting compounds of the present disclosure are more efficient than the individual targets The anti-HIV activity of the physical mixture of the fusion inhibitory polypeptide to gp41, the CCR5 small molecule inhibitor alone, the fusion inhibitory polypeptide targeting gp41, and the small molecule inhibitor of CCR5 was significantly improved, demonstrating that the fusion inhibitory polypeptide targeting gp41 with CCR5 The covalent attachment of the small molecule inhibitor indeed played a strong synergistic effect.

(2) The anti-HIV activities of compounds 4-1, 4-5, 4-6, and 4-7 are far superior to those of compounds 4-2, 4-3, and 4-4, and the anti-HIV activities of compounds 4-1 and 4 The anti-HIV activities of each of -2, 4-3, 4-4, 4-5, 4-6, and 4-7 were different from each other to varying degrees. This indicated that the presence or absence and length of the linker between the fusion inhibitory polypeptide targeting gp41 and the CCR5 small molecule inhibitor had a significant effect on the anti-HIV activity of the conjugated polypeptide.

(3) Compounds 4-9, 4-10, 4-11, 4-12, and 4-13 all effectively inhibited the R5 HIV strain Bal, which has a low nanomolar level of anti-HIV activity, and the effect is significantly better than that alone TAK-220/B07-F/LJC-240, the polypeptide shown in SEQ ID NO: 13 alone, a physical mixture of TAK-220/B07-F/LJC-240 and the polypeptide shown in SEQ ID NO: 13. Thus, fusion inhibitory polypeptides targeting gp41 (eg, the polypeptide set forth in SEQ ID NO: 13) were combined with various CCR5 small molecule inhibitors (eg, TAK-220, B07-F, LJC-240) After conjugation via covalent bonds, the resulting compounds of the present disclosure are more efficient than the gp41-targeting fusion inhibitory polypeptide alone, the CCR5 small molecule inhibitor alone, the gp41-targeting fusion inhibitory polypeptide and the physical mixture of the CCR5 small molecule inhibitor The anti-HIV activity was significantly improved, thus proving that covalently linking the gp41-targeting fusion inhibitory polypeptide to the CCR5 small molecule inhibitor indeed played a strong synergistic effect. HIVHIV

Example 5: Synthesis and Activity Testing of Compounds Containing SFT Polypeptides

Example 5-1: Synthesis of Compound 5-1

The difference between compound 5-1 and compound 1-1 is that SFT polypeptide is used instead of C34 polypeptide. For simplicity, the structure of compound 5-1 is roughly represented by "SFT polypeptide-K (PEG12-TAK)" in Table 7 below.

Example 5-2: Synthesis of Compound 5-2

The difference between compound 5-2 and compound 5-1 is that the PEG12-type flexible linking arm is removed. For simplicity, the structure of compound 5-2 is roughly represented in Table 7 below by "SFT polypeptide-K (TAK)".

Example 5-3: Synthesis of Compound 5-3

The difference between compound 5-3 and compound 5-1 is that a PEG4-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structure of compound 5-3 is roughly represented in Table 7 below as "SFT polypeptide-K (PEG4-TAK)".

Example 5-4: Synthesis of compound 5-4

The difference between compound 5-4 and compound 5-1 is that a PEG8-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 5-4 are roughly represented in Table 7 below as "SFT polypeptide-K (PEG8-TAK)".

Example 5-5: Synthesis of compound 5-5

The difference between compound 5-5 and compound 5-1 is that a PEG16-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 5-5 are roughly represented in Table 7 below as "SFT polypeptide-K (PEG16-TAK)".

Example 5-6: Synthesis of Compound 5-6

The difference between compound 5-6 and compound 5-1 is that a PEG20 type flexible linker is used instead of a PEG12 type flexible linker. For simplicity, the structures of compounds 5-6 are roughly represented in Table 7 below as "SFT polypeptide-K (PEG20-TAK)".

Example 5-7: Synthesis of compound 5-7

The difference between compound 5-7 and compound 5-1 is that a PEG24-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 5-7 are roughly represented in Table 7 below as "SFT polypeptide-K (PEG24-TAK)".

Comparative Example 5-1: Synthesis of Compound 5-8

The amino acid sequence of compounds 5-8 is shown in SEQ ID NO: 4, which is acetylated at the amino terminus and amidated at the carboxy terminus. For simplicity, the structures of compounds 5-8 are roughly represented in Table 7 below as "SFT polypeptides".

Examples 5-8: Anti-HIV activity test

HIV activity tests were performed as described in Examples 1-7 and the results are shown in Table 7.

Table 7: _EC50 of test compounds in CEMx174 5.25M7 cells infected with HIV strain Bal

The results show:

(1) Compounds 5-1, 5-2, 5-3, 5-4, 5-5, 5-6, and 5-7 all effectively inhibited the R5 HIV strain Bal, which has a low nanomolar level of resistance to HIV activity, the effect is significantly better than TAK-220 alone, SFT polypeptide alone, physical mixture of TAK-220 and SFT polypeptide, wherein compounds 5-1, 5-3, 5-5, 5-6, 5-7 show The anti-HIV activity exhibited is particularly outstanding, and the anti-HIV activity exhibited by compounds 5-3 and 5-6 is even better. It can be seen that after covalently conjugating a fusion inhibitory polypeptide (eg, SFT polypeptide) targeting gp41 to a small molecule inhibitor of CCR5 (eg, TAK-220), the resulting compounds of the present disclosure are more The anti-HIV activity of the physical mixture of the fusion inhibitory polypeptide to gp41, the CCR5 small molecule inhibitor alone, the fusion inhibitory polypeptide targeting gp41, and the small molecule inhibitor of CCR5 was significantly improved, demonstrating that the fusion inhibitory polypeptide targeting gp41 with CCR5 The covalent attachment of the small molecule inhibitor indeed played a strong synergistic effect.

(2) The anti-HIV activities of each of the compounds 5-1, 5-2, 5-3, 5-4, 5-5, 5-6, and 5-7 were different from each other to varying degrees. This indicated that the presence or absence and length of the linker between the fusion inhibitory polypeptide targeting gp41 and the CCR5 small molecule inhibitor had a significant effect on the anti-HIV activity of the conjugated polypeptide.

Example 6: Synthesis and Activity Testing of Compounds Containing HP23 Polypeptides

Example 6-1: Synthesis of Compound 6-1

The difference between compound 6-1 and compound 1-1 is that HP23 polypeptide is used instead of C34 polypeptide. For simplicity, the structure of compound 6-1 is roughly represented by "HP23 polypeptide-K (PEG12-TAK)" in Table 8 below.

Example 6-2: Synthesis of Compound 6-3

The difference between compound 6-3 and compound 6-1 is that a PEG4-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structure of compound 6-3 is roughly represented in Table 8 below as "HP23 polypeptide-K (PEG4-TAK)".

Example 6-3: Synthesis of compound 6-4

The difference between compound 6-4 and compound 6-1 is that a PEG8-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structure of compound 6-4 is roughly represented in Table 8 below as "HP23 polypeptide-K (PEG8-TAK)".

Example 6-4: Synthesis of compound 6-5

The difference between compound 6-5 and compound 6-1 is that a PEG16-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 6-5 are roughly represented in Table 8 below by "HP23 polypeptide-K (PEG16-TAK)".

Example 6-5: Synthesis of compound 6-6

The difference between compound 6-6 and compound 6-1 is that a PEG20-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 6-6 are roughly represented in Table 8 below as "HP23 polypeptide-K (PEG20-TAK)".

Example 6-6: Synthesis of compound 6-7

The difference between compound 6-7 and compound 6-1 is that a PEG24-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of Compounds 6-7 are roughly represented by "HP23 polypeptide-K (PEG24-TAK)" in Table 8 below.

Comparative Example 6-1: Synthesis of Compound 6-2

The difference between compound 6-2 and compound 6-1 is that the PEG12-type flexible linking arm is removed. For simplicity, the structure of compound 6-2 is roughly represented by "HP23 polypeptide-K (TAK)" in Table 8 below.

Comparative Example 6-2: Synthesis of Compound 6-8

The amino acid sequences of compounds 6-8 are shown in SEQ ID NO: 5, which are acetylated at the amino terminus and amidated at the carboxy terminus. For simplicity, the structures of Compounds 6-8 are roughly represented by "HP23 polypeptide" in Table 8 below.

Examples 6-7: Anti-HIV activity test

HIV activity tests were performed as described in Examples 1-7 and the results are shown in Table 8.

Table 8: _EC50 of test compounds in CEMx174 5.25M7 cells infected with HIV strain Bal

The results show:

(1) Compounds 6-1, 6-3, 6-4, 6-5, 6-6, and 6-7 all effectively inhibited the R5 HIV strain Bal, which has a low nanomolar level of anti-HIV activity, and the effect Significantly better than TAK-220 alone, HP23 polypeptide alone, physical mixture of TAK-220 and HP23 polypeptide, wherein compounds 6-1, 6-4, 6-5, 6-6, 6-7 exhibited anti-HIV The activity is particularly outstanding, and compounds 6-1, 6-5, and 6-7 show better anti-HIV activity. It can be seen that after covalently conjugating a fusion inhibitory polypeptide targeting gp41 (eg, HP23 polypeptide) to a small molecule inhibitor of CCR5 (eg, TAK-220), the resulting compounds of the present disclosure are more efficient than the individual targets The anti-HIV activity of the physical mixture of the fusion inhibitory polypeptide to gp41, the CCR5 small molecule inhibitor alone, the fusion inhibitory polypeptide targeting gp41, and the small molecule inhibitor of CCR5 was significantly improved, demonstrating that the fusion inhibitory polypeptide targeting gp41 with CCR5 The covalent attachment of the small molecule inhibitor indeed played a strong synergistic effect.

(2) The anti-HIV activity of compounds 6-1, 6-3, 6-4, 6-5, 6-6, and 6-7 is much better than that of compound 6-2, and compounds 6-1 and 6 The anti-HIV activities of each of -3, 6-4, 6-5, 6-6, and 6-7 were different from each other to varying degrees. This indicated that the presence or absence and length of the linker between the fusion inhibitory polypeptide targeting gp41 and the CCR5 small molecule inhibitor had a significant effect on the anti-HIV activity of the conjugated polypeptide.

Example 7: Synthesis and Activity Testing of Compounds Comprising CC Polypeptides

Example 7-1: Synthesis of Compound 7-1

The difference between compound 7-1 and compound 1-1 is that CC polypeptide is used instead of C34 polypeptide. For simplicity, the structure of compound 7-1 is roughly represented by "CC polypeptide-K (PEG12-TAK)" in Table 9 below.

Example 7-2: Synthesis of compound 7-2

The difference between compound 7-2 and compound 7-1 is that a PEG24-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structure of compound 7-2 is roughly represented by "CC polypeptide-K (PEG24-TAK)" in Table 9 below.

Example 7-3: Synthesis of Compound 7-3

The difference between compound 7-3 and compound 7-1 is that TAKW is used instead of TAK. The structural formula of TAKW is as follows:

The structural formula of compound 7-3 is shown below

For simplicity, the structure of compound 7-3 is roughly represented by "CC polypeptide-K (PEG12-TAKW)" in Table 9 below.

Example 7-4: Synthesis of compound 7-4

The difference between compound 7-4 and compound 7-3 is that a PEG24-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structure of compound 7-4 is roughly represented in Table 9 below as "CC polypeptide-K (PEG24-TAKW)".

Example 7-5: Synthesis of compound 7-5

The difference between compound 7-5 and compound 7-1 is that TAK is replaced by B07. The structural formula of B07 is as follows:

The structural formula of compound 7-5 is shown below

For simplicity, the structures of compounds 7-5 are roughly represented in Table 9 below as "CC polypeptide-K (PEG12-B07)".

Example 7-6: Synthesis of compound 7-6

The difference between compound 7-6 and compound 7-5 is that a PEG24-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 7-6 are roughly represented in Table 9 below as "CC polypeptide-K (PEG24-B07)".

Example 7-7: Synthesis of compound 7-7

The difference between compound 7-7 and compound 7-1 is that TAK is replaced by LJC. The structural formula of LJC is as follows:

The structural formula of compound 7-7 is shown below

For simplicity, the structures of compounds 7-7 are roughly represented in Table 9 below as "CC polypeptide-K (PEG12-LJC)".

Example 7-8: Synthesis of compound 7-8

The difference between compound 7-8 and compound 7-7 is that a PEG24-type flexible linker is used instead of a PEG12-type flexible linker. For simplicity, the structures of compounds 7-8 are roughly represented in Table 9 below as "CC polypeptide-K (PEG24-LJC)".

Comparative Example 7-1: Synthesis of Compound 7-9

The amino acid sequence of compounds 7-9 is shown in SEQ ID NO: 12, which is acetylated at the amino terminus and amidated at the carboxy terminus. For simplicity, the structures of compounds 7-9 are roughly represented in Table 8 below as "CC polypeptides".

Examples 7-9: Anti-HIV Activity Test

HIV activity tests were performed as described in Examples 1-7 and the results are shown in Table 9.

Table 9: _EC50 of test compounds in CEMx174 5.25M7 cells infected with HIV strain Bal

The results show:

(1) Compounds 7-1, 7-2, 7-3, 7-4, 7-5, 7-6, and 7-8 all effectively inhibited the R5 HIV strain Bal, which has a low nanomolar level of resistance to HIV activity, the effect is significantly better than TAK-220/B07-F/LJC-240 alone, CC polypeptide alone, physical mixture of TAK-220/B07-F/LJC-240 and CC polypeptide. It can be seen that after covalently conjugating fusion inhibitory polypeptides targeting gp41 (eg, CC polypeptides) with various small molecule inhibitors of CCR5 (eg, TAK-220, B07-F, LJC-240) , the resulting compounds of the present disclosure have significantly improved anti-HIV activity over a physical mixture of a gp41-targeting fusion inhibitory polypeptide, a single CCR5 small molecule inhibitor, a gp41-targeting fusion inhibitory polypeptide and a CCR5 small molecule inhibitor, Thus, it is proved that covalently linking the fusion inhibitory polypeptide targeting gp41 with the CCR5 small molecule inhibitor indeed has a strong synergistic effect.

(2) The anti-HIV activity of compound 7-8 is much better than that of compound 7-7, and compound 7-1 and 7-2, 7-3 and 7-4, 7-5 and 7-6, 7 The respective anti-HIV activities of -7 and 7-8 differed from each other to varying degrees. This indicates that the length of the linker between the fusion inhibitory polypeptide targeting gp41 and the small molecule inhibitor of CCR5 has a significant effect on the anti-HIV activity of the conjugated polypeptide.

Claims

A compound of formula (I)

or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein

P represents a fusion inhibitory polypeptide targeting gp41;

SM stands for CCR5 small molecule antagonist;

L 1 is optional and represents a flexible link arm;

L is optional and represents a flexible link arm ;

A represents one or more amino acid residues;

α is optionally present and is selected from the group consisting of acetyl, maleyl, succinyl, tert-butoxycarbonyl, benzyloxycarbonyl, dansyl or other hydrophobic or macromolecular carrier groups, and is associated with the amino terminal residue of P. base direct connection;

β is optionally present, selected from amino or other hydrophobic groups or macromolecular carrier groups, and is directly attached to the carboxy-terminal residue in A;

When L 1 is present, the amino-terminal residue of A is directly linked to L 1 ; when L 1 is absent, the amino-terminal residue of A is directly linked to P;

When L2 is present, the side chain of A is directly connected to L2 ; when L2 is not present, the side chain of A is directly connected to SM.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein the P is SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 , SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:11, SEQ ID NO:12 or SEQ ID NO:13 of fusion inhibitory polypeptides targeting gp41.
The compound of claim 2, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein the SM is selected from 4-piperidine-1-propylamines, 1,4-diamines Residues of substituted piperazines or tropanes.
The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein the SM is selected from the residues of the following compounds:

Wherein Ac represents acetyl; Me represents methyl; R 1 represents -F, -Cl, -CN, -CF 3 or -SO 2 CH 3 ; R 2 represents (CH2) p N 3 , p is between 1-10 the integer.
The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein said L 1 , L 2 independently represent -NH-( CH 2 CH 2 O) m -(CH 2 ) n -C(=O)-, m is an integer between 1-30, n is an integer between 1-3; or the L 1 and L 2 are each other independently represents (GGGGS) y , (GGGS) y , (GSG) y or (GSGSG) y , where y is an integer between 1-6.
The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein only one of said L 1 and L 2 is present.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein said A comprises at least one amino acid having an active group on its side chain Residues.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein α is acetyl.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein β is amino.
A composition comprising the compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.
The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the composition of claim 10, in the manufacture of a prophylactic or Use in medicines for the treatment of AIDS.