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Application of a compound in preparing anti-virus medicament

An anti-AIDS and drug technology, applied in drug delivery, antiviral agents, pharmaceutical formulations, etc., can solve problems such as anti-HIV virus CypA inhibitors that have not been reported yet

Inactive Publication Date: 2008-01-23
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, so far, no one has reported CypA inhibitors with anti-HIV

Method used

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  • Application of a compound in preparing anti-virus medicament
  • Application of a compound in preparing anti-virus medicament
  • Application of a compound in preparing anti-virus medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Virtual Screening of CypA Small Molecule Inhibitors

[0031] The Cyclophilin A (CypA, PPIA) gene has been registered in the Human Genome Database, and its accession number is NM_021130. In the PDB protein structure database, we retrieved the X-ray diffraction crystal structure of human CypA protein (PDB code: 1CWA). This structure is the crystal structure of CypA in complex with its natural inhibitor cyclosporin A (CsA). From this structure, we determined the active site of CypA, and identified several key amino acid sites in the active site that can be inhibited by CsA. Based on these structural information, we cooperated with the Shanghai Institute of Materia Medica, Chinese Academy of Sciences to screen several small molecule databases for the active site of CypA. The small molecule databases used for screening mainly include SPECS and CNPD. Finally, FD8 of the present invention was screened. The whole calculation process is carried out on the 64CPU-SGI...

Embodiment 2

[0032] Example 2 Utilizes BIAcore Molecular Interaction Instrument to Verify Virtual Screening Results

[0033] The BIAcore molecular interaction instrument is based on surface plasmon resonance technology to track the interaction between biomolecules without any markers, thus ensuring the authenticity of the experimental results to the greatest extent. During the experiment, the target biomolecules (CypA ​​protein) were immobilized on the surface of the sensor chip, and then the small molecule compounds were dissolved in the solvent and flowed over the surface of the chip. The monitor can track the changes in the whole process of binding and dissociation between molecules in the detection solution and target biomolecules on the chip surface in real time. Based on the binding data of BIAcore, we finally identified 12 small molecular compounds that can bind to CypA, and calculated the equilibrium-dissociation constant KD of the binding of these small molecular compounds to CypA...

Embodiment 3

[0034] Example 3 Proves the ability of small molecule compounds to inhibit CypA enzyme activity by using enzyme activity experiments

[0035] There are many methods for measuring CyP activity, but α-chymotrypsin-coupled enzymic assay is the most commonly used.

[0036] We took the reaction without small molecule inhibitors as the control reaction, measured the inhibition rate of each small molecule ligand on the enzyme activity reaction at different concentrations, and calculated the IC50 value of each small molecule ligand. N-[4-(N-{5-[(2,3-dihydro-1H-inden-5-yloxy)methyl]-2-furyl}acetylhydrazino)phenyl]cyclopentyl of the present invention Alkanecarboxamides (CHEMCATS Order Number: AK-968 / 15604391). Its enzyme activity inhibition IC 50 Values ​​([mu]M) were 18.67±1.74, eg, 16.84, 18.86 or 20.3.

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Abstract

The invention relates to the technical field of chemical industry, in particular to a preparation method and application of micromolecule compound with HIV resisting activity. CyPA is able to combine with the Gag polymer protein in HIV-1. Silence or inhibit the activity of CypA with RNAi technology and disturb the replication of virus. The micromolecule compound in the invention refers to a CyPA inhibitor that has the effect of resisting HIV-1 virus. Besides, as the micromolecule compound is designed while aiming at cellular target, the invention is not easy to develop drug resistance, thus meeting the demands of lifetime medication for AIDS patients. Therefore, the micromolecule compound in the invention, which can be developed as a new type anti-AIDS drug, provides a new means for treating and curing AIDS.

Description

technical field [0001] The invention relates to the fields of chemical industry and medicine, and relates to the application of a compound in the preparation of anti-AIDS drugs. Background technique [0002] Cycliphilins (CyPs) are ubiquitously distributed intracellular proteins that are highly conserved in plants, bacteria, and mammals. They were originally discovered as cellular receptors for cyclosporin A. Cyclosporin A (Cyclosporin A, CsA) is a cyclic polypeptide containing 11 amino acids isolated from fungal metabolites. As an immunosuppressant drug, it is often used clinically to treat rejection and autoimmune system after organ transplantation. disease. There are more than 130 isomers of CyPs that have been discovered and cloned [GalatA, Metcalfe SM. Peptidyl proline cis-trans iso-merases. Prog Biophys Molec Biol, 1995; 63: 67.], which constitute the Cyclophilins family. CyPs has peptide prolyl cis-trans isomerase (PPIase) activity, catalyzes the protein folding pro...

Claims

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Application Information

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IPC IPC(8): A61K31/341A61K9/20A61K9/08A61P31/18
Inventor 余龙陈帅赵雪梅蒋华良唐丽莎
Owner FUDAN UNIV
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