Double-target anti-HIV (anti-human immunodeficiency virus) glycopeptide compound and application thereof

A compound and oligosaccharide technology, which is applied in the direction of peptides, decapeptides, antiviral agents, etc., can solve the problems of high cost, long time, and low success rate

Active Publication Date: 2016-01-27
INST OF MICROBIOLOGY - CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, it takes a long time and a high cost to discover a new drug, and the success rate is low, while structural modification and structural modification of existing drugs is an important way to obtain n

Method used

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  • Double-target anti-HIV (anti-human immunodeficiency virus) glycopeptide compound and application thereof
  • Double-target anti-HIV (anti-human immunodeficiency virus) glycopeptide compound and application thereof
  • Double-target anti-HIV (anti-human immunodeficiency virus) glycopeptide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1, the synthesis of mannopentaose

[0021]

[0022] Weigh compound 1 (prepared according to the document J.Carbohydr.Chem., 2006, 25, 491-498, 3.67mmol) in a 100ml reaction bottle, add 10ml of dichloromethane solvent, and add 40ml of MeOH solvent to dissolve the raw material, 40 ℃ oil Heating in a bath, adding excess AcCl to carry out selective deprotection reaction, concentrating the reaction solution, and passing through a silica gel column for separation and purification to obtain compound 2 with a yield of 85%. 1 HNMR (500MHz, CDCl 3 ): δ5.98(t, J=9.9Hz, 1H, H-4), 5.63(dd, 1H, H-3), 5.46(s, 1H, H-1), 4.79-4.77(m, 1H, H-5),4.60(dd,J 6a,5 =2.3Hz,J 6a,6b =12.05Hz,1H,H-6a),4.54(dd,J 6b,5 =5.55Hz,J 6b,6a =12.05Hz,1H,H-6b),4.42(s,1H,H-2),2.77-2.65(m,2H,SC H 2 ), 1.34(t, J=7.35Hz, C H 3 );+cESI-MSforC 29 h 28 o 8 S + ,[M] + , Calcd: 536.150, Found: 536.148.

[0023]

[0024] Weigh compound 2 (0.128mmol) in the reaction flask, equipped with a...

Embodiment 2

[0029] Embodiment 2, the synthesis of sugar chain

[0030]

[0031] Under nitrogen protection, compound 7 or 8 (obtained according to the literature J.Org.Chem., 2005,70,9809-9813) or 9 (according to the literature BeilsteinJ.Org.Chem., 2010,6,801-809) or 10 (according to Literature Biomacromolecules, 2012,13,3039-3045 obtained) (0.224mmol) and compound 15 (obtained according to literature J.Med.Chem., 2015,58,1372-1379, 1.0~2.0eq) mixture was dissolved in 2 / 1 In tetrahydrofuran / water (4.5ml in total), under stirring at room temperature, add copper sulfate pentahydrate (the amount of copper sulfate pentahydrate added accounts for 5% of the molar weight of compound 7 or 8 or 9 or 10), then add sodium ascorbate (ascorbic acid The amount of sodium added accounted for 5% of the molar amount of compound 7 or 8 or 9 or 10), and transferred to 35°C oil bath reaction, after 18h, TLC (developing solvent was ethyl acetate / methanol / water of 5 / 2 / 1.5) It was found that the reaction of ...

Embodiment 3

[0036] Example 3, Glycosylation modification of polypeptide (that is, synthesis of M1-T20, M3-T20, M5-T20 and Lex-T20)

[0037] The amino acid sequence of the T20 polypeptide is shown in sequence 1 in the sequence listing. Polypeptide cT20 was purchased from Polypeptide Synthesis Company, and its amino acid sequence is shown in sequence 2 in the sequence listing. The polypeptide cT20 is obtained by adding a cysteine ​​before the nitrogen-terminal amino acid tyrosine of the T20 polypeptide, and the newly added cysteine ​​residue serves as the site of glycosylation reaction.

[0038] The sugar chains 11-14 prepared above were connected to the nitrogen-terminal amino acid cysteine ​​of the polypeptide cT20 through a highly chemoselective Michael addition reaction, and the specific process was as follows.

[0039] Dissolve the mixture of 0.006 mmol of sugar chains 11 to 14 obtained in Example 2 and 0.002 mmol of polypeptide cT20 in 5 ml of sodium dihydrogen phosphate / disodium hyd...

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PUM

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Abstract

The invention discloses a double-target anti-HIV (anti-human immunodeficiency virus) glycopeptide compound and an application thereof. The anti-HIV glycopeptide compound is a T20 compound modified with mannan oligosaccharide or oligosaccharide containing fucose at the terminal. The fixed-point glycosylated modified compound of an anti-HIV drug represented as M1-T20, M3-T20, M5-T20 or Lex-T20 is a double-target drug, can prolong the plasma half-life of the drug in the animals and enhance the HIV inhibiting effect, and has the great application value.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a dual-target anti-HIV glycopeptide compound and its application. Background technique [0002] Since it was first discovered in 1981, the prevention and treatment of AIDS has not been effectively addressed. AIDS is caused by human immunodeficiency virus (HIV) infection, and its extremely high fatality rate poses a great threat to human life and health. At present, there has been an explosive epidemic trend in the world. According to the statistics of the Ministry of Health of my country, as of the end of 2011, it is estimated that the number of living HIV-infected and AIDS patients (PLHIV) in China has reached 780,000 (620,000-940,000). . Due to the high mutation rate of the virus, no effective vaccine has yet been found. [0003] As the world's first invasion inhibitor, T20 (also known as enfuvirtide (enfuvirtide), trade name Fuzeon) was approved by the US FDA in 2003, and it is also th...

Claims

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Application Information

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IPC IPC(8): C07K14/00A61K38/16A61P31/18
CPCA61K38/00C07K14/00
Inventor 李学兵程水红王彦马丽英邵一鸣
Owner INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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