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Key amino acid locus for regulating and controlling A type and B type influenza virus nucleoprotein to export nuclear and application thereof in anti-influenza virus drug target spot

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

Active Publication Date: 2019-03-15
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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  • Key amino acid locus for regulating and controlling A type and B type influenza virus nucleoprotein to export nuclear and application thereof in anti-influenza virus drug target spot
  • Key amino acid locus for regulating and controlling A type and B type influenza virus nucleoprotein to export nuclear and application thereof in anti-influenza virus drug target spot
  • Key amino acid locus for regulating and controlling A type and B type influenza virus nucleoprotein to export nuclear and application thereof in anti-influenza virus drug target spot

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0097] Example 1 Influenza virus nucleoprotein Y148 residues affect ANP out of nucleus

[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 in which the 148th amino acid of the wild-type ANP sequence is mutated to alanine and phenylalanine, respectively.

[0101] The above wild-type ANPs were cloned into pcDNA4TO (Invitrigen, catalog number V103020), pCMV-MYC (Clontech, catalog number 635689) and expression vector pHH21 (from the gift of Professor Yoshihiro Kawaoka, University of Wisconsin-Madison, USA). The vector is 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 influenza virus reverse genetic packaging system. The pHH21 vector has a pr...

Embodiment 2

[0114] Example 2 Type A influenza virus nucleoprotein Y148 residue affects type A influenza virus replication and virulence

[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, PerezDR, Donis R, Hoffmann E, Hobom G, Kawaoka Y., Generation of influenza A viruses entirely from cloned cDNAs, Proc Natl Acad Sci US A.1999,96(16): 9345-50, replace the NP-containing related vector with the A-ANP wild-type fragment, A-Y148A mutant fragment or A-Y148F prepared in Example 1 The pHH21 vector of the mutant fragment implements the rescue of the recombinant influenza A virus. Utilize Lipofectamine TM 2000 transfection. After 6 hours of transfection, the medium was changed, 2 μg / ml serum-free DMEM containing TPCK-treated pancreatin (SIGMA, article number T1426) was added, and the supernatant was harvested after 72h-96h of culture.

[0117] Two, plaque test to detect virus titer

[0118] C...

Embodiment 3B

[0137] Example 3 Influenza B virus nucleoprotein F209 residues affect the nucleation of influenza B virus nucleoprotein

[0138] 1. Research on key sites of influenza B virus nucleoprotein (BNP)

[0139] The structure of BNP and ANP are very similar. 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, etc., Structural basis for RNA binding and homo-oligomer formation by influenza B virus nucleoprotein, Journal of virology. 2012; 86(12): 6758 -67). The sequence alignment results showed 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 function to A-Y148 during the...

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PUM

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Abstract

The invention relates to a key amino acid locus for regulating and controlling A type and B type influenza virus nucleoprotein to export nuclear and application thereof in an anti-influenza virus drugtarget spot, and also relates to a medicinal composition for treating A type or B type influenza virus. The medicinal composition comprises a compound for regulating and controlling the A type and Btype influenza virus nucleoprotein to export nuclear.

Description

Technical field [0001] The invention belongs to the field of biomedicine, and relates to the key amino acid sites for regulating the nucleoprotein of type A and type B influenza viruses and their use as anti-influenza virus drug targets. The present invention also relates to a pharmaceutical composition for the treatment of type A or type B influenza virus infection, the pharmaceutical composition comprising a compound that regulates the nucleation of type A or type B influenza virus nucleoprotein. Background technique [0002] Type A and Type B influenza viruses belong to the Orthomyxoviridae family. Influenza A virus (influenza A) can infect humans and a variety of animals. Various subtypes of influenza A viruses have high pathogenicity and / or high mortality, which seriously threaten the health of animals and humans. Influenza B virus (influenza B) mainly infects humans. Although the pathogenicity to humans is relatively low, pneumonia caused by influenza B virus infection o...

Claims

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Application Information

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Patent Type & Authority Applications(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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