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Conjugated molecules for the treatment of AIDS comprising a peptide derived from a CD4 receptor coupled to a polyanionic polypeptide

A technology of anionic polypeptides and conjugated molecules, which can be used in medical preparations containing active ingredients, medical preparations without active ingredients, receptors/cell surface antigens/cell surface determinants, etc. question

Inactive Publication Date: 2016-05-11
INST PASTEUR +2
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mutations in either of these two sites will indeed result in a less infectious virus

Method used

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  • Conjugated molecules for the treatment of AIDS comprising a peptide derived from a CD4 receptor coupled to a polyanionic polypeptide
  • Conjugated molecules for the treatment of AIDS comprising a peptide derived from a CD4 receptor coupled to a polyanionic polypeptide
  • Conjugated molecules for the treatment of AIDS comprising a peptide derived from a CD4 receptor coupled to a polyanionic polypeptide

Examples

Experimental program
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Effect test

Embodiment 1

[0165] Embodiment 1: Synthesis of conjugated molecules of the present invention

[0166] 1.1 Synthesis of peptides of formula H-γ-Abu-SXDXSXDXSXDXS-OH, wherein X=YSO3 (P3YSO3), Y(P3Y), Asu(P3Asu), or pF(P3pF); H-γ-Abu-SY SO3 Dy SO3 Sy SO3 DYSYDYS-OH (Nter3 Sulfate); H-γ-Abu-SYDYSYDY SO3 Sy SO3 Dy SO3 S-OH (Cter3 Sulfate); and H-γ-Abu-(Glu) 13 -OH(E13); where γ-Abu:NH 2 -(CH 2 ) 3 -CO.

[0167] The following examples describe the synthesis of modified peptides of formula H-γ-Abu-SXDXSXDXSXDXS-OH, wherein X=YSO3(P3YSO3), Y(P3Y), Asu(P3Asu) or pF(P3pF); H-γ-Abu-SY SO3 Dy SO3 Sy SO3 DYSYDYS-OH (Nter3 Sulfate); H-γ-Abu-SYDYSYDY SO3 Sy SO3 Dy SO3 S-OH (Cter3 Sulfate); H-γ-Abu-(Glu) 13 -OH(E13); where γ-Abu:NH 2 -(CH 2 ) 3 -CO. In this formula, the anionic peptides of the present invention (except peptide E13) correspond to SXDXSXDXSXDXS-OH (SEQ ID NO: 19), wherein X is as above (same or different).

[0168] The resulting modified peptide is:

[0169] P3YSO3 (SEQ...

Embodiment 2

[0196] Embodiment 2: Biacore evaluation

[0197] 2.1. Operation

[0198] Two different gp120s were employed, derived from an X4-type isolate (gp120MN) and an R5-type isolate (gp120YU2). The ability of different molecules to inhibit the interaction of gp120 with various receptors or co-receptors was measured by surface plasmon resonance (Biacore).

[0199] For this, proteins (in this case gp120 envelope protein) can be immobilized on the surface of a biosensor (Sensorchip CM4Biacore) according to the procedure described (Vivès et al. J. Biol. Chem. 279, 54327-54333, 2005) . When injected onto surfaces coated with the MN(X4) or YU2(R5) gp120 envelope, mCD4 binds and exposes the CD4i epitope on gp120 responsible for the envelope binding of mAb17b ( Figure 5 A) (mAb17b antibody recognizes CD4-induced epitopes and mimics co-receptors CCR5 or CXCR4). The interaction signal between gp120 and mAb17b was measured as a function of time when mCD4 or the compound to be tested was inj...

Embodiment 3

[0211] Embodiment 3: the antiviral activity of peptide of the present invention to X4-tropism HIV-1-LAI and R5-tropism HIV-1 / Ba-L strain

[0212] 3.1. Operation

[0213] Antiviral activity was performed as described in WO / 2009 / 098147 and Nature Chemical Biology, 2009, 5(10), 743-748.

[0214] Briefly, X4-tropic HIV-1-LAI was expanded and titrated in vitro on phytohemagglutinin-P (PHA-P)-activated peripheral blood mononuclear cells (PBMC) (Barre-Sinoussi, Science 220, 868 -71, 1983) or R5-tropic HIV-1 / Ba-L (Gartner et al., Science 233, 215-9, 1986) strain. use The formula for calculating the tissue culture infection dose ( Arch. Exp. Path. Pharmak. 162, 480-483, 1931). For antiviral assays, PHA-P-activated PBMCs were pretreated for 30 min with six concentrations of each drug (diluted 1:5 between 0.5 μM and 160 pM) and treated with X4-tropic LAI or R5-tropic Ba - Infection with one hundred and 50% tissue culture infectious dose (TCID50) of the L strain. Drugs were maintai...

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Abstract

The present invention relates to conjugated molecules comprising a peptide derived from the CD4 receptor coupled to an organic molecule via a linker and a method for their preparation. The organic molecules include anionic polypeptides of 5 to 21 amino acids. The conjugated molecule can be used for antiviral therapy, that is, for the treatment of AIDS.

Description

technical field [0001] The present invention relates to conjugated molecules comprising a peptide derived from the CD4 receptor and an organic molecule, such as a polyanionic polypeptide. The conjugated molecule can be used for antiviral therapy, that is, for the treatment of AIDS. The invention further relates to methods of preparing said conjugated molecules. Background technique [0002] Triple therapy combining nucleosides (NRTIs), non-nucleosides (NNRTIs), and / or protease inhibitors (PIs) resulted in reductions in viral load (viral charge) below detectable levels in a large number of seropositive HIV patients. These treatments target both reverse transcription and proteolysis. This efficacy has resulted in a substantial reduction in the number of deaths caused by HIV infection. But unfortunately, about 80% of the patients showed antiviral resistant genotypes, and more worryingly, 45.5% of the viral populations were resistant to NRTI / PI combination therapy, while 26% ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/48C07K14/705A61P31/18
CPCC07K14/70514C07K14/70539C07K2319/00A61K47/6425A61K38/195A61K38/16A61K38/177A61P31/18C07K17/02
Inventor F·巴勒斯克H·洛尔塔雅各布D·博纳夫
Owner INST PASTEUR
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