Ns1 protein inhibitors
a technology of ns1 protein and inhibitor, which is applied in the field of virology, molecular biology and medicine, can solve the problems of unsatisfactory availability of additional therapeutic modalities for the treatment of influenza viral diseases, limited efficacy of vaccination, and unsatisfactory availability of additional therapeutic modalities, so as to inhibit the cytopathic effect of influenza a virus, reduce the severity or duration of viral infection symptoms, and reduce the severity or duration of viral infection
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example 1
NS1 Protein Binds Host mRNA Export Factors Blocking Expression of Antiviral Genes
[0109]NS1 protein forms an inhibitory complex with the mRNA export factors NXF1-p15, Rae1, and E1B-AP5 (Satterly et al., 2007), which are key constituents of the mRNA export machinery that interact with both mRNAs and nucleoporins, such as Nup98, to direct mRNAs through the nuclear pore complex (NPC) (Stutz and Izaurralde, 2003) (FIG. 1B). The mRNA export receptors NXF1-p15 (TAP-NXT) are responsible for nuclear exit of ˜70% of cellular mRNAs (Stutz and Izaurralde, 2003). This heterodimer interacts with both messenger ribonucleoprotein particles (mRNPs) and nuclear pore complex proteins (nucleoporins or Nups) to translocate mRNAs through the NPC (Stutz and Izaurralde, 2003). E1B-AP5, identified as a cellular protein that interacts with the adenovirus protein E1B-55 (Geiss et al., 2002), is an hnRNP-like protein that likely mediates the interaction of NXF1 with mRNAs (Bachi et al., 2000). Furthermore, the...
example 2
Influenza Virus Inhibits Host Poly(A) RNA Nuclear Export—Part I
[0111]The NS1 protein of influenza virus has been shown to inhibit nuclear export of host mRNAs when expressed in mammalian cells (Qiu and Krug, 1994). To examine the importance of regulated bulk mRNA export in the context of viral infection, the distribution of host poly(A) RNA in influenza virus infected MDCK cells was determined, and nuclear export was found to be impaired (FIG. 2A). Expression of influenza proteins in MDCK cells was clearly detected by immunoblot analysis, starting at 4 hours post-infection (FIG. 2B). Inhibition of mRNA export was observed as early as 6 h post-infection (FIG. 2A), a time that allowed easy detection of infected cells using polyclonal antibodies against influenza proteins. However, this inhibitory effect on mRNA export may begin even earlier, as a key constituent of the mRNA export machinery is degraded at early stages of infection (see below). The inhibition of mRNA export was enhance...
example 3
Influenza Virus Inhibits Host Poly(A) RNA Nuclear Export—Part II
[0112]Whether NS1 protein interacted with the mRNA nuclear export machinery was investigated. Purified GST-NS1 protein or GST alone was incubated with cell extracts from 293T cells. As shown in FIG. 3A, NS1 protein interacted with NXF1, p15, E1B-AP5 and Rae1. In contrast, no interaction of NS1 protein was detected with other constituents of the nuclear transport machinery including Nup96, Nup62, Nup153, and Nup214 (FIGS. 3B and 3C). These results indicate that NS1 protein binds specifically to the mRNA factors NXF1, p15, E1B-AP5, and Rae1, which are known to form a complex (Bachi et al., 2000; Blevins et al., 2003).
[0113]The first 73 amino acids of NS1 protein bind dsRNA with low affinity (Krug et al., 2003) and amino acids 19 to 38 are required for NS1 protein-mediated inhibition of mRNA nuclear export as are amino acids 134 to 161 at the carboxyl terminus (Qian et al., 1994). Deletion of the first 48 or 72 amino acids...
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