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Artificially designed anti-HIV infection polypeptide, composition and use

A composition and application technology, applied in the fields of anti-HIV infection polypeptide, treatment or prevention of related diseases caused by HIV infection, non-physiologically toxic salt, acquired immunodeficiency syndrome, and can solve the problem of low bioavailability and drug resistance , limit the wide application of T20 and other issues

Inactive Publication Date: 2017-12-29
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the discovery of T-20 has opened up a new field of using peptide drugs to control HIV, due to some defects and deficiencies in itself, the wide application of T20 is limited.
The first is drug resistance. Since T20 is completely derived from the natural sequence of gp41, it is highly sensitive to target mutations. The mutation of a single amino acid residue in the target sequence will reduce the activity of T20 by 10 times, and the mutation of two residues will reduce its activity. 100 times
Therefore, although the natural sequence of T20 maintains the structure of the natural ligand to the greatest extent, the virus is prone to drug resistance to T20 due to the high mutation of the target HIV-1 gp41 sequence
Secondly, T20 is easily degraded by protease and has low bioavailability in vivo

Method used

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  • Artificially designed anti-HIV infection polypeptide, composition and use
  • Artificially designed anti-HIV infection polypeptide, composition and use
  • Artificially designed anti-HIV infection polypeptide, composition and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0141] Embodiment 1: the preparation of compound 6

[0142] A standard Fmoc solid-phase peptide synthesis method was used. All peptide sequences are amidated at the C-terminus and acetylated at the N-terminus. Rink Amide resin is selected, the amino acid is in L configuration, and the peptide chain is extended from the C-terminus to the N-terminus. The condensing agent is HBTU / HOBt / DIEA. The deprotecting agent is piperidine / DMF solution. The lysing agent is trifluoroacetic acid (TFA), and the crude peptide is dissolved in water and then freeze-dried for storage. Separation and purification are carried out by medium-pressure liquid chromatography Flash or high-pressure liquid chromatography (HPLC), and the pure peptide content is >95%. Matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS) confirmed the molecular weight of the peptide sequence.

[0143] Use CEM automatic microwave peptide synthesizer for peptide synthesis, the synthesis conditions...

Embodiment 2-68

[0154] Embodiment 2-68: Preparation of Compound 1-5, 7-68

[0155] Compounds No. 1-No. 5, No. 7-No. 68 were synthesized according to the method of Example (1), and the amino acids were all in L configuration, but the corresponding amino acid residues were replaced.

Embodiment 69

[0156] Example 69: Inhibition of HIV-1 Biological Activity Detection

[0157] Evaluation of compounds inhibiting HIV-1-mediated cell-cell fusion activity (IC 50 ):

[0158] Detection of HIV-1-Mediated Cell-Cell Fusion by Stain Transfer Assay: HIV-1 IIIB Infected H9 cells (H9 / HIV-1 IIIB ) was labeled with a fluorescent reagent Calcein-AM (Molecular Probes, Inc., Eugene, OR), and then, 50 μl of labeled H9 / HIV-1 was added to each well of a 96-well plate mB cells (2×10 5 / ml), and then add 50 μl of different concentrations of test samples (compounds prepared in the tested examples 1-34 and 44-53, two-fold serial dilution from a concentration of 250 μg / ml), and incubate at 37°C for 30min; then each well Add 100ul of MT-2 cells (1×10 6 / ml), incubated at 37°C for 2h. Confused and unfused Calcein-labeled HIV-1 infected MT-2 cells (MT-2 is a commonly used effector cell used in this experiment to simulate HIV-infected target cells, commercially available) with an inverted fluores...

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PUM

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Abstract

Provided in the present invention are a polypeptide and the derivative and stereoisomer or salt without physiological toxicity thereof as shown in formula I. The polypeptide is an artificially designed anti-HIV infection polypeptide. Also provided in the present invention are pharmaceutical compositions containing the polypeptide and the derivative and stereoisomer or salt without physiological toxicity thereof, and the use of the polypeptide and the derivative and stereoisomer or salt without physiological toxicity thereof in treating or preventing related diseases caused by the HIV infection.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to an artificially designed, non-natural sequence anti-HIV infection polypeptide, in particular, to the polypeptide represented by formula I, its derivatives, its stereoisomers, or its non-physiologically toxic Salt. The present invention also relates to a pharmaceutical composition containing the above-mentioned polypeptide of formula I, its derivative, its stereoisomer, or its non-physiologically toxic salt, and the formula I polypeptide, its derivative, its stereoisomer, or its Use of the non-physiologically toxic salt in the treatment or prevention of related diseases caused by HIV infection, especially acquired immunodeficiency syndrome (AIDS, namely AIDS). [0002] x a1 AAX d1 x e1 BB-X a2 AAX d2 x e2 BB-X a3 AAX d3 x e3 BB-X a4 AAX d4 x e4 BB-X a5 AAX d5 x e5 BB Formula I. Background technique [0003] AIDS is currently prevalent in the world and poses a serious thre...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/00A61K38/16A61P31/18
CPCA61K38/16A61P31/18
Inventor 刘克良史卫国王潮蔡利锋贾启燕王昆郑保华张沙白玉
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A