Structure and Activities of the NS1 Influenza Protein and Progress in the Development of Small-Molecule Drugs

Abstract

The influenza virus causes human disease on a global scale and significant morbidity and mortality. The existing vaccination regime remains vulnerable to antigenic drift, and more seriously, a small number of viral mutations could lead to drug resistance. Therefore, the development of a new additional therapeutic small molecule-based anti-influenza virus is urgently required. The NS1 influenza gene plays a pivotal role in the suppression of host antiviral responses, especially by inhibiting interferon (IFN) production and the activities of antiviral proteins, such as dsRNA-dependent serine/threonine-protein kinase R (PKR) and 2'-5'-oligoadenylate synthetase (OAS)/RNase L. NS1 also modulates important aspects of viral RNA replication, viral protein synthesis, and virus replication cycle. Taken together, small molecules that target NS1 are believed to offer a means of developing new anti-influenza drugs.

Keywords: NS1; drug; influenza virus A; inhibitor; small molecule.

Figure 1

Structural analyses of NS1. (A) Schematic representation of the full-length NS1 domain and of interacting proteins. NS1 consists of an RNA-binding domain (RBD), a linker region (LR), an effector domain (ED), and a C-terminal tail (CTT). RBD binds to dsRNA to inhibit the interferon (INF) induction, whereas the C-terminal ED region mediates interactions with several host cellular proteins. (B) NS1 dimer adapted from the X-ray structure of H6N6 NS1 (PDB ID: 4OPA), showing interactions between the two RBD.

Figure 2

Overview of the functions of NS1 protein in cytoplasm and nuclei of infected cells. NS1 plays a vital role as an INF antagonist for the influenza virus. NS1 inhibits IFN induction at the pre-transcriptional stage by blocking the activation of the RIG-I and at the post-translational level by repressing activations of the antiviral properties of PKR and OAS/RNase L. Furthermore, NS1 disrupts the processing and nuclear export of cellular mRNAs. NS1 enhances viral mRNA translation, and activation of the PI3K pathway by NS1 is required for viral replication in infected cells.