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Cholesterol modified anti-human immunodeficiency virus (HIV) polypeptide medicament and application thereof

A technology of cholesterol and modifiers, which is applied in the field of cholesterol-modified anti-HIV polypeptide drugs and their applications, which can solve the problems of easy drug resistance, limited application, and difficulty in developing into drugs due to water solubility, and achieve good water solubility and long half-life , easy to synthesize effects

Inactive Publication Date: 2011-09-14
INST OF PATHOGEN BIOLOGY CHINESE ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, T-1249 stopped clinical trials due to problems with the dosage form
T-20 is the first and currently the only HIV-1 membrane fusion inhibitor approved for clinical treatment, but its clinical application is limited due to its tendency to cause drug resistance
Although C34 has better activity, it is difficult to develop into a drug due to its water solubility

Method used

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  • Cholesterol modified anti-human immunodeficiency virus (HIV) polypeptide medicament and application thereof
  • Cholesterol modified anti-human immunodeficiency virus (HIV) polypeptide medicament and application thereof
  • Cholesterol modified anti-human immunodeficiency virus (HIV) polypeptide medicament and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1. Synthesis and modification of peptides

[0049] 1.1 Materials

[0050] The required chemical reagents were all obtained from major chemical reagent suppliers and used without further purification. Rink resin (with a substitution constant of 0.44 mmol / g) was purchased from Tianjin Hecheng Company.

[0051] 1.2 Polypeptide synthesis

[0052] All peptides were synthesized by solid-phase peptide synthesis (Fmoc / tBu strategy), manually synthesized from the carboxy-terminus to the amino-terminus.

[0053] Amino acid protected by N-fluorenylmethoxycarbonyl (Fmoc), Rink resin (substitution constant is 0.44mmol / g) is used as a solid phase carrier, and the amino protecting group is removed with a DMF solution of 25% (volume percentage) piperidine For Fmoc, each removal step needs to be carried out twice, and the duration is 8min and 10min respectively. The condensation methods used for the peptide grafting reaction were DIPC / HOBt method and PyBOP method. The amin...

Embodiment 2

[0068] Example 2. Evaluation of antiviral effect of CHFI polypeptide

[0069] 2.1 Inhibitory effect of polypeptide on HIV strain NL4-3: The molecular cloning plasmid pNL4-3 encoding HIV-1 strain NL4-3 was provided by NIH AIDS Research & Reference Reagent Program (catalogue number: 114). The pNL4-3 plasmid was prepared using the plasmid extraction kit from QIAGEN, and Lipofectamine from Invitrogen TM 2000 Transfection Reagent Transfect the pNL4-3 plasmid into 293T cells at 37°C in 5% CO 2 After 6 hours of incubation in the cell culture incubator, the medium was changed, and then culture was continued for 48 hours. Gently collect the supernatant in the cell culture flask or cell culture plate with a pipette, filter the supernatant through a 0.45 μm filter, add 20% fetal bovine serum (FBS), then divide into polypropylene tubes, and place at -80 Store at ℃ for later use or titrate the virus directly. The steps of virus titration are as follows: the virus is diluted 5 times in...

Embodiment 3

[0083] Example 3. CHFI polypeptide has significant activity against HIV drug-resistant strains

[0084] Amino acid mutations in the NHR region of HIV fusion protein gp41 can lead to virus resistance to fusion inhibitors. To further evaluate the anti-HIV activity of CHFI, we used a set of HIV gp41 natural mutant strains and induced mutant strains in Table 4 to test the inhibitory effect of CHFI on viral infection. Natural mutant strains include L33S, L33M, L33V, S35F, Q39R, L54M, Q56K, Q56R, L54M / Q56K, L54M / Q56R and L34M / L54M / Q56R, the preparation method of which is shown in the published literature of people such as Chinnadurai (Raghavan Chinnadurai, Jan Mu¨nch and Frank Kirchhoff. Effect of naturally-occurring gp41 HR1 variations on susceptibility of HIV-1 to fusion inhibitors. AIDS 2005, 19: 1401-1405); induced mutants include I37Q / V38M, I37Q / V38Q, I37S / V38N and I37V / V38T, its preparation method is shown in the literature published by Chinnadurai et al. Ex Vivo Human Lym...

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Abstract

The invention discloses a cholesterol modified anti-human immunodeficiency virus (HIV) polypeptide medicament and application thereof. The cholesterol modified anti-HVI polypeptide is named CHFI, and the amino acid sequence of the polypeptide is shown as the sequence 2 in a sequence table, wherein the cysteine residue at the 33rd position of the sequence 2 is connected with cholesterol through a thioether bond. Bromoacetic acid cholesterol ester is grafted to the side chain of polypeptide chain cysteine by thioether formation reaction with extremely high chemical selectivity to obtain the CHFI. The CHFI has the important advantages of strong anti-virus activity, targeting property, long half-life period, good water solubility and the like, and is easily synthesized.

Description

technical field [0001] The present invention relates to a kind of polypeptide drug for inhibiting human immunodeficiency virus (HIV) efficiently, its design method and application for treating AIDS. Background technique [0002] At present, there are more than 60 million HIV-infected people in the world, and about 20 million of them have died. The number of new infections and deaths is increasing every year. According to WHO estimates, there are now 16,000 new infections every day; it is estimated that about 100 million people will be infected in ten years, which will undoubtedly be a catastrophe for human society. Vaccine is the best way to prevent AIDS, but for more than two decades, no clinical program of HIV vaccine has been proven effective. In a fairly long period of time in the future, it may be difficult to have a major breakthrough in an effective HIV vaccine. Therefore, vigorously studying the mechanism of HIV-1 infection and designing drugs that block the diffe...

Claims

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Application Information

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IPC IPC(8): C07K14/00C12N15/11C12N15/63C12N5/10C12N1/00C12N7/01C07K1/107A61K38/16A61K39/00A61P31/18
CPCY02P20/55
Inventor 何玉先种辉辉张超
Owner INST OF PATHOGEN BIOLOGY CHINESE ACADEMY OF MEDICAL SCI
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