WO2011127624A1

WO2011127624A1 - Anti-hiv peptide

Info

Publication number: WO2011127624A1
Application number: PCT/CN2010/000488
Authority: WO
Inventors: 刘克良; 姜世勃; 贾启燕; 史卫国; 白玉; 冯思良; 康晓宇; 杨琛; 张沙; 郑保华
Original assignee: 中国人民解放军军事医学科学院毒物药物研究所
Priority date: 2010-04-13
Filing date: 2010-04-13
Publication date: 2011-10-20

Abstract

The present invention provides an anti-HIV peptide, which comprises the amino acid sequence of AA1-AA2-Val-AA4-Leu-AA6. The present invention also provides a preparation method of the peptide and use related to inhibition of HIV infection.

Description

Anti-HIV peptide

Technical field

The present invention relates to a hexapeptide and a derivative thereof for alleviating or inhibiting HIV infection, a process for the preparation thereof, a pharmaceutical composition containing the same, and their use in the treatment or prevention of acquired immunodeficiency syndrome (AIDS) and HIV infection Uses related to the disease. Background technique

The process by which HIV infects a target cell begins with the fusion of the viral envelope with the target cell membrane, and then the viral genetic material RNA enters the target cell, replicating and releasing the new virus. The entry of HIV into target cells is mediated by the viral envelope glycoprotein complex (gpl20/gp41) and receptors on target cells (CD4 receptor and chemokine receptor CCR-5 or CXCR-4). First, the surface subunit gpl20 of the HIV envelope glycoprotein binds to the CD4 receptor on the target cell and attaches to the cell; it then binds to the co-receptor of the target cell (chemokine receptor CCR5 or CXCR4, etc.); The conformation of the subunit gp41 is altered, and the N-terminal fusion peptide is inserted into the host cell membrane to initiate fusion of the viral envelope with the target cell membrane to complete the infection process of the virus into the host cell 2003, 348: 2228-33). Inhibition of any of the above steps can prevent HIV from entering the target cells, thereby preventing and treating HIV infection.

In recent years, with the deepening of research on the mechanism of HIV membrane fusion, research on drugs that inhibit HIV from entering target cells has progressed very rapidly. These drugs are called HIV entry inhibitors. Due to the key role of gp41 in the membrane fusion process, it has become a new target for the development of anti-HIV drugs. Such drugs targeting gp41 are called HIV fusion inhibitors.

In 2007, Frank Kirchhof f reported a class of resistance with new targets. HIV fusion inhibitor, VIRIP and its derivatives (Cel l, 2007, Vol. 129, 293-275), wherein VIRIP is a peptide of 20 amino acids. Such compounds specifically bind to the fusion peptide region (FP) of Gp41, thereby blocking the fusion process of HIV with host cells and inhibiting viral replication.

The object of the present invention is to find an anti-HIV substance having a lower molecular weight, a higher biological activity and a better metabolic property. Summary of the invention

The present inventors have found through research that the hexapeptide of the formula (I) or a derivative thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, has a good activity for inhibiting HIV-infected target cells. Therefore, the polypeptide of the formula (I) or a derivative thereof, a stereoisomer thereof or a salt thereof which is not physiologically toxic can be used as a medicament for the treatment or prevention of HIV infection.

A first aspect of the invention relates to a hexapeptide of formula I or a derivative thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

R -AA ₁ -AA ₂ -Val-AA ₄ -Leu-AA ₆ -R ₂ Formula (I)

among them

May be a natural or non-natural hydrophobic amino acid or deletion of type D or L; AA ₂ may be a natural or non-natural aromatic amino acid or deletion of type D or L; AA ₄ may be a natural type D or L Or a non-natural aromatic amino acid;

Everyone ₆ can be a natural or unnatural amino acid or a deletion of type D or L;

1^ is 11, Ac-, ureido- or 1-10 amino acid residues;

R ₂ is -0H, -NH2 or 1-10 amino acid residues;

! ^ or R ₂ may be further amidated, alkylated, acylated, ureaylated, PEGylated. Further, in the present invention, AAi is preferably L or D proline, hydroxyproline or pyroglutamic acid;

AA ₂ and/or AA ₄ are each independently preferably L or D phenylalanine, 4-aminophenylalanine, 4-chlorophenylalanine, naphthylalanine, β-piperonyl alanine , morpholinylphenylalanine or p-ureidophenylalanine;

ΑΑ ₆ is preferably methionine, serine, glutamine, aspartic acid, asparagine, lysine or arginine.

The amino acid residues in R and R ₂ are preferably 1, 2, 3 or 4, and include, but are not limited to, aspartic acid, asparagine, isoleucine, glutamic acid or glutamine.

1 is a sequence of 11, Ac -, Ureido - or 1-10 amino acid residues;

R ₂ is a sequence of -0H, -NH2 or 1-10 amino acid residues;

According to a preferred embodiment of the invention, the hexapeptide of the invention or a derivative thereof is selected from the following peptides or stereoisomers thereof or pharmaceutically acceptable salts thereof:

(1) Ac- -Pro ¹ - -Phe ² - -Val ³ - -Phe ⁴ - -Leu-Met ⁶

(2) Ac- -Pro ¹ - -Phe ² - -Val ³ - -Phe ⁴ - -Leu ⁵ -NH ₂

(3) Ac- -Pro ¹ - -Phe ² - -Val ³ - -Phe ⁴ - -NH ₂

(4) Ac- -Pro ¹ - -Phe ² - -Val ³ - -NH ₂

(5) Ac- -Phe ¹ - -Val ² - ■Phe ³ - -Leu ⁴ - -Met ⁵ -NH ₂

(6) Ac- -Phe ¹ - -Val ² - ■Phe ³ - -Leu ⁴ - -NH ₂

(7) Ac- ■Phe ¹ - -Val ² - -Phe ³ - -NH ₂

(8) Ac- -Val ¹ - -Phe ² - -Leu ³ - -Met ⁴ - - NH ₂

(9) Ac- -Val ¹ - -Phe ² - -Leu ³ - -NH ₂

(10) Ac-Phe -Leu -Met ³ -NH ₂

(11) Ac-D-Pro-D-Phe -D-Val -D-Phe -D-Leu-D-Met -NH ₂

(12) Ac-Pro-Phe ² -Val ³ -Phe-Leu ⁵ -Ser ⁶ -NH ₂

(13) Ac-Pro-Phe-Val -Phe-Leu-Gln-NHj

(14) Ac-Pro-Phe ² -Val ³ -Phe ⁴ -Leu ⁵ -Asp ⁶ -NH ₂ Ac-Pro -Phe -Val -Phe-Leu-Lys -NH ₂

22222221 1 Ac-Pro -Phe ² -Val ³ -Phe ⁴ -Leu ⁵ -Asn ⁶ -NH ₂

^ 53

Ac-Pro -Na 1 ² -Va 1 ³ -Phe ⁴ -Leu ⁵ -Me t ⁶ -NH ₂

Ac-Pro -Phe ² -Val ³ -Nal -Leu ⁵ -Met ⁶ -NH ₂

Ac-Pro -Nal ² -Val ³ -Nal -Leu ⁵ -Met ⁶ -NH ₂

-Mop ² - Va 1 ³ -Phe ⁴ -Leu ⁵ -Me 1 ⁶ -NH ₂

-Phe-Val -Mop ⁴ -Leu ⁵ -Met ⁶ -NH ₂

Ac-Pro -Mop -Va 1 ³ -Mop ⁴ -Leu ⁵ -Me 1 ⁶ -NH ₂

Pgl -Phe-Val -Phe-Leii-Met-N^

Ureido-Pro-Phe ² -Val ³ -Phe ⁴ -Leu ⁵ -Met ⁶ -NH ₂ Ac-Pro-Phe-Val ³ -Phe ⁴ -Leu ⁵ -Met ⁶ -Cys ⁷ -OH Ac-Asp-Pro ² - Phe ³ -Val ⁴ -Phe ⁵ -Leu ⁶ -Met ⁷ -NH ₂ Ac-Asn-Pro ² -Phe ³ -Val ⁴ -Phe ⁵ -Leu ⁶ -Met ⁷ -NH ₂ Ac-Pro-Phe-Val -Phe ⁴ -Leu ⁵ -Met ⁶ -Iln ⁷ -NH ₂ Ac-Pro-Phe-Val-Phe-Leu-Met-Iln-Glu-NHa Ac-Pro-Phe ² -Val ³ -Phe ⁴ -Leu ⁵ -Met ⁶ -Iln ⁷ -Glu ⁸ -Gln ⁹ -NH ₂

Ac-Pro-Phe -Val -Phe-Leu-Met-Iln-Glu-Gln-

Asn ¹ -NH

(32: Ac-D-Met -D-Leu-D-Phe -D-Val -D-Phe -D-Pro -NH (33) Ac-Pro-D-Phe-Val -D-Phe-Leu'- Met-NHj More preferred polypeptides of the invention are the numbered (1), (8), (9) and (32) hexapeptides or derivatives thereof.

A further aspect of the invention relates to a pharmaceutical composition comprising at least one hexapeptide of formula (I) or a derivative thereof or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. The invention further relates to the use of a hexapeptide of the formula I or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or condition associated with HIV infection, such as AIDS.

The invention further relates to a process for the preparation of a hexapeptide of the formula I or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which process comprises

固 using solid phase synthesis method, using Rink Amid resin as carrier, Fmoc-protection strategy, DCC/H0BT or HBTU/H0BT as condensation reagent, piperidine/DMF as deprotection reagent, according to the amino acid sequence of the prepared target (compound) From the C-terminus to the N-terminus, the peptide resin was synthesized according to the standard Fmoc solid phase peptide synthesis method. The above peptide resin was placed in a 250 ml eggplant-shaped glass reaction flask, and 10 ml of the lysate I was added under ice bath. The lysate I formula: TFA: anisole: m-cresol: ethanedithiol: water = 7. 5: 1 0. 5: 0. 5: 0. 5, stirring in a water bath for 30 minutes, stirring to room temperature and stirring for 90 minutes, adding 100 ml of cold anhydrous ether, suction filtration to obtain a white solid, dissolved in water, suction filtration, and the filtrate was freeze-dried. The term "derivative" of the present invention includes the deletion of 1, 2, or 3 amino acids of the hexapeptide of formula (I), or the addition of 1, 2, 3 or 4 amino acids at either or both ends of the hexapeptide.

The term "stereoisomer of a hexapeptide of the formula (I) or a derivative thereof" as used in the present invention means its corresponding D- or L-stereo configuration.

In the present invention, the polypeptide is generally a hexapeptide, but the hexapeptide may have an amino acid deletion and become a tri-, tetra- or pentapeptide; or 1-10, preferably 1-4 amino acids, at either or both ends of the hexapeptide. , becomes seven, eight, nine or ten peptides.

According to the present invention, the pharmaceutical composition of the present invention can be prepared by a conventional method in the art, for example, by mixing a hexapeptide of the formula I or a derivative thereof with a pharmaceutically acceptable carrier or excipient. The pharmaceutically acceptable carrier or excipient used in the present invention is usually a pharmaceutically acceptable carrier or excipient which is commonly used in the pharmaceutical field. The polypeptide of formula I of the invention may be used alone or in the form of a pharmaceutical composition. The method of administration can be oral or parenteral. Oral route of administration can be a tablet, glue 嚢 or granules, etc. The parenteral preparation can be an injection, a spray, a patch or the like. The composition of the present invention can also be formulated into sustained release preparations such as microspheres and the like. detailed description

The abbreviations used in the present invention have the following meanings:

Ac (Acetyl) acetyl

AIDS (Acquired Immure Deficiency Syndrome) AIDS, Acquired Immune Deficiency Syndrome

Ala (Alanine, A) Alanine

Arg (Arginine, R) arginine

Asn (Asparagine, N) Asparagine

Asp (Aspartic acid, D) aspartic acid

Boc (t-Butoxycarbonyl) tert-butoxycarbonyl

CDI (N^'-Carbonyldi imidazole) carbonyl diimidazole

CHR (C-terminal heptad repeat) C-terminal repeat

Cpa 4-chlorophenylalanine

DCC (N, N-Dicyclohexy lcarbodi imide) dicyclohexylcarbodiimide

DCM (Dichloromethane) Dichloromethane

DIEA (N, N-Di isopropylethylamine) N,N-diisopropylethylamine

DMF (N, N-Di methyl malonate) Dimercaptoamide

Env (envelope glycoprotein) envelope glycoprotein

Fmoc (Fluorenylmethoxycarbonyl) fluorenylmethoxycarbonyl

Gln (Glutamine, Q) glutamine

Glu (Glutamic acid, E) glutamic acid

HBTU 2-(1Η-1 -hydroxybenzotriazole)-1, 1, 3, 3-tetramethyluron

His (Histidine, H) HoBt (1-Hydroxylbenzotriazole anhydrous) 1 - ^ and trinitrogen

HIV (Human immunodeficiency Virus)) human immunodeficiency virus

HIV-1 human immunodeficiency virus type I

HIV-2 human immunodeficiency virus type II HPLC (High performance liquid chromatography) high performance liquid chromatography

He (Isoleucine, I) Isoleucine

Leu (Leucine, L) leucine

Lys (Lysine, K) Lysine

MBHA phenylaminomethyl resin

MS mass spectrometry

Mob β-piperonyl alanine

Mop morpholinyl phenylalanine

Nal naphthylalanine

NHR (N-terminal heptad repeat) N-terminal repeat 歹

Phe (Phenylalanine, F) Phenylalanine

Ser (Serine, S) Serine

TFA (trif luoroacetic acid) trifluoroacetic acid

TLC (Thin-layer chromatography)

Thr (Threonie, T) Threonine

Trp (Tryptophan, W) Tryptophan

Tyr (Tyrosine, Y) Tyrosine

Uph (4-Ureido-phenylalanine) 4-ureidophenylalanine Example

The following examples and biologically active faces are used to further illustrate the invention, but this is not intended to limit the invention in any way. The solid phase synthesis carrier MBHA resin used in the examples is Tianjin Nankai Synthetic Co., Ltd.; DCC;, H0BT, HBTU, DIEA and Fmoc protected natural amino acids or D-type unnatural amino acids are Shanghai Jill Biochemical Co., Ltd. and Chengdu Chengnuo New Technology Limited liability company products. Example 1: Synthesis of Compound (1)

0. 3g MBHA resin (0. 48mmol) as a solid phase carrier, DCC/HOBt or HBTU/DIEA as a condensing agent, according to the amino acid sequence of the polypeptide of formula I to be obtained, from the C terminal to the N terminal, according to the standard Fmoc solid Phase peptide synthesis methods (Reference: Huang Weide, Chen Changqing, Peptide Synthesis, Science Press, 1985) The synthesis of Ac-PFVFLM-MBHA resin.

After condensing methionine, leucine, phenylalanine, valine, phenylalanine, and valine, and then capping with oxalic anhydride and DIEA, the above peptide resin is placed in the HF cutter. In the reactor, 1.0 mL of anisole was added. After the installation, the system of the HF cutter was evacuated, and the reactor was cooled with liquid nitrogen, and transferred to about 10 mL of liquid HF for 40 minutes. The HF was pumped off with an oil pump, the reactor was removed, solidified with chilled anhydrous diethyl ether, and the suspension was transferred to a sand core funnel. It was washed three times with a small amount of cooled anhydrous diethyl ether, washed with an aqueous solution until the resin no longer adhered to each other, and the washing liquid was collected, and lyophilized to obtain a white dry powder. The compound (1) was purified by RP-HPLC. MS: 795. 1 (theoretical value: 794). Example 2: Synthesis of Compound (9)

0. 25g Rink Amid resin (0.50 leg ol) as a solid phase carrier, DCC/HOBt or HBTU/DIEA as a condensing agent, according to the amino acid sequence of the prepared compound, from the C terminal to the N terminal, according to the standard Fmoc solid Phase peptide synthesis method (Reference: Huang Weide, Chen Changqing, Peptide Synthesis, Science Press, 1985) Operational Synthesis of VFL-Rink Amid Resin.

The leucine, phenylalanine and proline were sequentially condensed, and then blocked with oxalic anhydride and DIEA. The above peptide resin was placed in a 250 ml eggplant-shaped glass reaction flask, and 10 ml of lysate I was added thereto under ice bath to lyse. Liquid I formula: TFA: anisole: m-cresol: ethanedithiol: water -7. 5: 1: 0. 5: 0. 5: 0. 5 , stirring in ice bath for 30 min, stirring to room temperature and stirring for 90 min After adding 100 ml of cold anhydrous ethyl ether, a white solid was obtained by suction filtration, and the mixture was dissolved in water, and filtered, and the filtrate was lyophilized to obtain white dry powder (0. 27 g), which was purified by RP-HPLC to give compound (9). MS: 419. 0 (theoretical value 418.5).

The following polypeptides were synthesized in the same manner as in Example 9 using the amino acids in the corresponding compound numbers:

16 777. 5 776. 9

20 893. 6 893. 6

21 893. 9 893. 6

23 766. 5 766. 1

25 898. 7 898. 2

26 908. 6 908. 1

27 909. 5 909. 1

28 907. 5 907. 2

29 1036. 7 1036. 3

30 1165. 0 1164. 4

31 1278. 1 1278. 5

32 794. 5 794

33 794. 1 794 Example 4: Synthesis of compound (24)

1. Synthesis of tert-butylcarbamoyl valine

Add 100 ml of methanol to the eggplant type bottle, add 7.4 ml of acetyl chloride to the ice bath for 30 min, remove the ice bath and add 4 g of L-valine (L-valine: acetyl chloride (molar ratio) = 1: 3). , 60. The oil was refluxed for 6 hours in a C-br., evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Further, 7 ml of N,N-diisopropylethylamine (DIEA) and 200 ml of DCM were added and stirred for 10 min to obtain a decyl decyl ester. 2. 82g carbonyl diimidazole (CDI) was dissolved in DCM to clarify in an eggplant bottle, and 2 ml of t-butylamine was added dropwise under ice bath (tert-butylamine: CDI: L-valine methyl ester hydrochloride = 1. 1 : 1 : 2) , After the dropwise addition, the reaction was stirred at room temperature for 30 min to obtain tert-butylaminocarbonylimidazole. tert-Butylaminocarbonylimidazole and proline methyl ester 50: Re-distilled in an oil bath for 8 h. The reaction solution was extracted twice with 1N hydrochloric acid to obtain a DCM layer. The mixture was extracted with water and brine, dried over anhydrous magnesium sulfate, and then evaporated to dryness to give white crystals of succinyl carbamoyl decanoyl ester (M = 214) 1. 93 g (yield 52%) Rf=0 . 61 (DCM: MeOH: HAc-20: 1: 0. 5).

H-NMR (DMS0-D ₆ , 400MHz, δ ppm): 1. 24 (S, 9H) , 1. 84 (m, 3H) , 2. 05 (m, H) , 3. 35 (m, 2H) , 4. 17 (d, H, J=7. 2) , 5, 38 (s, H) , 12. 32 (s, H)

2. Synthesis of Compound (24)

0. 25g R ink Amid resin (0.50 leg ol) as a solid phase carrier, DCC/HOBt or HBTU/DIEA as a condensing agent, according to the amino acid sequence of the prepared compound, from the C terminal to the N terminal, according to the standard Fmoc Solid phase peptide synthesis methods (References: Huang Weide, Chen Changqing, Peptide Synthesis, Science Press, 1985) The synthesis of Rink Amid resin.

After sequentially condensing methionine, leucine, phenylalanine, valine, phenylalanine, and t-butylaminoproline valine, the peptide resin is blocked with oxalic anhydride and DIEA. Put into a 250 ml eggplant-shaped glass reaction flask, add 10 ml of lysate I under ice bath, lysate I formula: TFA: phenyl oxime: m-cresol: ethanedithiol: water = 7. 5: 1 : 0. 5 : 0. 5: 0. 5 , stirring in ice bath for 30 min, stirring to room temperature and stirring for 90 min, adding 100 ml of cold anhydrous ether, suction filtration to obtain white solid, dissolved in water, suction filtration, and the filtrate was freeze-dried to obtain white dry powder. Purified by RP-HPLC. MS: (theoretical value). Example 4: Inhibition of HIV-1 biological activity assay.

HIV-1 replication test

The inhibitory activity of the polypeptide of the present invention acting on the HIV-1 II IB complex was detected in MT-2 cells. In 200 μL of 1640 medium containing 10% fetal bovine serum, 1 10 ⁴ One MT-2 cell was transfected with one HIV-1 strain (100 TCID50), and the test compound was added according to the set concentration (blank group was not added) overnight. Thereafter, the culture supernatant j was removed, and the culture solution to which the test compound was not added was replaced. On the fourth day after transfection, 100 μl of the culture supernatant was collected per well, and the same volume of 5% Triton®-100 was added, and the yield of p24 antigen was measured by the quantitative Elisa method and the IC50 value was calculated. The recombinant p24 protein kit was purchased from US Biological (Swamps cot t, MA).

According to the above method, the activity measurement results are shown in Table 1.

Claims

Rights request

A hexapeptide of the formula (I) or a derivative thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof

R -AA -AA ₂ -Va l-AA ₄ -Leu-AA ₆ -R ₂ Formula (I)

among them

a natural or non-natural hydrophobic amino acid which may be D-form or L-form;

AA ₂ and/or AA ₄ may be a D- or L-type natural or non-natural aromatic amino acid;

AA ₄ is a natural or non-natural aromatic amino acid of type D or L;

May be a D or L natural or unnatural amino acid;

Is 11, Ac-, ureido- or 1-10 amino acid residues;

R ₂ is -0H, -NH2 or 1-10 amino acid residues;

R, and R ₂ may be further selectively amidated, alkylated, acylated, ureaylated, PEGylated.

2. The hexapeptide derivative of the formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein

Human is L or D proline, hydroxyproline or pyroglutamic acid;

AA ₂ and/or AA ₄ are each independently L or D type phenylalanine, 4-aminophenylalanine, 4-chlorophenylalanine, naphthylalanine, β-piperonyl alanine, Morpholinylphenylalanine or p-ureidophenylalanine;

ΑΑ ₆ is methionine, serine, glutamine, aspartic acid, asparagine, lysine or arginine;

And the amino acid residue in 11 ₂ is 1, 2, 3 or 4, and is selected from the group consisting of: aspartic acid, asparagine, isoleucine, glutamic acid or glutamine.

3. The hexapeptide of the formula (I) or a derivative thereof or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, is selected from the group consisting of:

(1) Ac-Pro -Phe -Va l -Phe'-Leu -Met -NH (2) Ac- Pro ¹ -■Phe ² -Val ³ -Phe ⁴ -■Leu ⁵ - ,NH ₂

(3) Ac-Pro ¹ - Phe-Val -Phe ⁴ - ■NH ₂

(4) Ac-Pro ¹ - Phe ² -Val ³ -NH ₂

(5) Ac-Phe ¹ - Val -Phe-Leu ⁴ - ■Met ⁵ - NH ₂

(6) Ac-Phe ¹ - Val -Phe-Leu- •NH ₂

(7), Ac-Phe ¹ - ■Val ² -Phe ³ -NH ₂

(8) Ac-Val ¹ - Phe-Leu-Met ⁴ - NH ₂

(9) Ac-Val ¹ - Phe ² -Leu ³ -NH ₂

(10) Ac-Phe ¹ -Leu-Met ³ -NH ₂

(11) Ac-D-Pro'-D-Phe-D-Va 1 -D- Phe ⁴ - D-Leu

(12) Ac-Pro ¹ -Phe ² -Val ³ -Phe ⁴ -Leu ⁵ -Ser ⁶ -NH ₂

(13) Ac-Pro ¹ -Phe -Val -Phe ⁴ -Leu ⁵ -Gin ⁶ -NH ₂

(14) Ac-Pro ¹ -Phe-Val -Phe ⁴ -Leu ⁵ -Asp ⁶ -NH ₂

(15) Ac-Pro ¹ -Phe-Val -Phe ⁴ -Leu ⁵ -Lys ⁶ -NH ₂

(16) Ac-Pro ¹ -Phe -Val -Phe ⁴ -Leu ⁵ - Asn ⁶ - NH ₂

(17) Ac-Pro ¹ -Nal -Val -Phe ⁴ -Leu ⁵ -Met ⁶ -NH ₂

(18) Ac-Pro ¹ -Phe ² -Val ³ -Nal ⁴ -Leu ⁵ -Met ⁶ -NH ₂

(19) Ac-Pro ¹ -Nal -Val -NaT -Leu ⁵ -Met ⁶ -NH ₂

(20) Ac-Pro ¹ -Mop-Val -Phe ⁴ -Leu ⁵ -Met ⁶ -NH ₂

(21) Ac-Pro ¹ -Phe ² -V l ³ -Mop ⁴ -Leu ⁵ -Met ⁶ -NH ₂

(22) Ac-Pro ¹ -Mop ² -Val ³ -Mop ⁴ -Leu ⁵ -Met ⁶ -NH ₂

(23) Pg 1 -Phe ² -Va 1 ³ -Phe ⁴ -Leu ⁵ -Met ⁶ -NH I

(24) Ureido- -Pro-Phe ² -Val ³ - -Phe ⁴ - -Leu ⁵ - ■Met ⁶ -

(25) Ac-Pro ¹ -Phe ² -Val ³ -Phe ⁴ -Leu ⁵ -Met ⁶ -Cys ⁷ -

(26) Ac-Asp ¹ -Pro-Phe-Val ⁴ -Phe ⁵ -Leu ⁶ - -Met ⁷ -

(27) Ac-Asn ¹ -Pro ² -Phe ³ -Val ⁴ -Phe ⁵ -Leu ⁶ -Met ⁷ - (28) Ac-Pro-Phe-Val-Phe -Leu ⁵ -Met ⁶ -Iln ⁷ -NH ₂

(29) Ac-Pro-Phe-Va 1 -Phe ⁴ -Leu ⁵ -Me t ⁶ - 11 n ⁷ -G 1 u ⁸ -NH ₂

(30) Ac-Pro-Phe-Val-Phe-Leu-Met -Iln-Glu-Gln'-NHj

(31) Ac-Pro-Phe-Val -Phe-Leu-Met -Iln-Glu-Gln- Asn ¹⁰ -NH ₂

(32) Ac-D-Met-D-Leu-D-Phe-D-Val -D-Phe-D-Pro-NHz

(33) Ac-Pro-D-Phe ² -Val ³ -D-Phe-Leu -Met ⁶ -NH ₂

A pharmaceutical composition comprising at least one hexapeptide according to any one of claims 1 to 3 or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

5. The hexapeptide of the formula (I) or a derivative thereof, or a stereoisomer or salt thereof, according to any one of claims 1 to 3, for use in the preparation of a medicament for the treatment or prevention of a disease associated with HIV infection, such as AIDS the use of.