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The key amino acid sites regulating nuclear export of influenza virus type a and b virus and their use as anti-influenza virus drug targets

A technology of influenza virus and nucleoprotein, applied in the field of biomedicine, can solve the problem of unclear key sites of NP entry/exit of type A influenza virus

Active Publication Date: 2022-08-02
INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Naproxen is a class of non-steroidal anti-inflammatory drugs. It is mainly used clinically for the treatment of arthritis (such as rheumatism and rheumatoid arthritis, osteoarthritis), ankylosing spondylitis, gout or tenosynovitis, etc. It can also be used for Relieve pain caused by musculoskeletal sprains, contusions, injuries, and dysmenorrhea. It has not been reported that the drug can be used in antiviral therapy
[0006] In addition, the current research is not clear about the key sites involved in vRNP nuclear import / export in influenza A virus NP, and there are no reports on which sites in influenza B virus NP (BNP) can be used as drug targets

Method used

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  • The key amino acid sites regulating nuclear export of influenza virus type a and b virus and their use as anti-influenza virus drug targets
  • The key amino acid sites regulating nuclear export of influenza virus type a and b virus and their use as anti-influenza virus drug targets
  • The key amino acid sites regulating nuclear export of influenza virus type a and b virus and their use as anti-influenza virus drug targets

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0097] Example 1 Influenza virus type A nucleoprotein Y148 residue affects the nuclear export of ANP

[0098] 1. Vector construction

[0099] Construction of wild-type influenza A virus nucleoprotein (ANP) and its Y148 residue mutant:

[0100] The wild-type ANP has the amino acid sequence shown in NCBI No. ACF54602.1; the A-Y148A and A-Y148F mutant fragments are sequences obtained by mutating the 148th amino acid of the wild-type ANP sequence to alanine and phenylalanine, respectively.

[0101]The above-mentioned wild-type ANPs were cloned into pcDNA4TO (Invitrigen, product catalog number V103020), pCMV-MYC (Clontech, product catalog number 635689) and expression vector pHH21 (from the gift of Professor Yoshihiro Kawaoka, University of Wisconsin-Madison, USA, the Vectors are described in "Neumann G, et al., Generation of influenza A viruses entirely from cloned cDNAs, Proc Natl Acad Sci US A. 1999;96(16):9345-50"). pHH21 and pcDNA4TO belong to the reverse genetic packaging s...

Embodiment 2

[0114] Example 2 Influenza A virus nucleoprotein Y148 residue affects replication and pathogenicity of influenza A virus

[0115] 1. Rescue of recombinant influenza A virus containing A-Y148 mutation

[0116]Using Neumann G, Watanabe T, Ito H, Watanabe S, Goto H, Gao P, Hughes M, Perez DR, Donis R, Hoffmann E, Hobom G, Kawaoka Y., Generation of influenza A virusesentirely from cloned cDNAs, Proc Natl Acad Sci US A. 1999, 96(16): 9345-50 according to the method described, replacing the NP-containing related vector with A-ANP wild-type fragment, A-Y148A mutant fragment or A-Y148F prepared in Example 1 The pHH21 vector of the mutated fragment implements the rescue of recombinant influenza A virus. Utilize Lipofectamine TM 2000 transfections. After 6 h of transfection, the medium was changed, and serum-free DMEM containing 2 μg / ml of TPCK-treated trypsin (SIGMA, Cat. No. T1426) was added, and the supernatant was harvested after culturing for 72 h to 96 h.

[0117] 2. Plaque as...

Embodiment 3B

[0137] Example 3 Influenza B virus nucleoprotein F209 residue affects the nuclear export of influenza B virus nucleoprotein

[0138] 1. Study on the key site of nuclear export of influenza B virus nucleoprotein (BNP)

[0139] The structure of BNP is very similar to that of ANP. In particular, both contain an RNA-binding groove rich in basic amino acids (Ye Q, Krug RM, Tao YJ., The mechanism by which influenza A virus nucleoproteinforms oligomers and binds RNA, Nature. 2006;444(7122): 1078-82. Ng AK, Lam MK, Zhang H, Liu J, Au SW, Chan PK, et al. Structural basis for RNA binding and homo-oligomer formation by influenza B virus nucleoprotein, Journal ofvirology. 2012;86(12):6758 -67). The sequence alignment results show that there is an aromatic amino acid in the RNA binding groove of ANP and BNP, Y148 of ANP and F209 of BNP ( Figure 5 A), and the sequence homology near these two sites is very high ( Figure 5 B). Therefore, we speculate that B-F209 may also play a similar...

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Abstract

The invention relates to the key amino acid sites for regulating the nuclear export of influenza A and B influenza virus nucleoproteins and their use as anti-influenza virus drug targets. The present invention also relates to a pharmaceutical composition for the treatment of influenza A or B virus infection, the pharmaceutical composition comprising a compound that modulates the nuclear export of influenza A or B virus nucleoprotein.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to the key amino acid sites for regulating the nuclear export of influenza A and B influenza virus nucleoproteins and their use as anti-influenza virus drug targets. The present invention also relates to a pharmaceutical composition for the treatment of influenza A or B virus infection, the pharmaceutical composition comprising a compound that modulates the nuclear export of influenza A or B virus nucleoprotein. Background technique [0002] Influenza A and B viruses belong to the family Orthomyxoviridae. Influenza A virus can infect humans and various animals. Influenza A viruses of various subtypes have high pathogenicity and / or high mortality, and seriously threaten the health of animals and humans. Influenza B virus (influenza B) primarily infects humans. Although relatively low pathogenic in humans, pneumonia caused by influenza B virus infection often has a high mortality rate. On...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61P31/16C12Q1/02
CPCA61K45/00G01N33/5008A61P31/16C12Q1/02A61K38/162A61K31/405G16B15/10G16B15/30G16B5/00C12Q1/70
Inventor 刘文军孙蕾郑伟楠李晶杨利敏范文辉
Owner INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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