The influenza virus NS1 protein as a therapeutic target

Abstract

Nonstructural protein 1 (NS1) of influenza A virus plays a central role in virus replication and blockade of the host innate immune response, and is therefore being considered as a potential therapeutic target. The primary function of NS1 is to dampen the host interferon (IFN) response through several distinct molecular mechanisms that are triggered by interactions with dsRNA or specific cellular proteins. Sequestration of dsRNA by NS1 results in inhibition of the 2’-5’ oligoadenylate synthetase/RNase L antiviral pathway, and also inhibition of dsRNA-dependent signaling required for new IFN production. Binding of NS1 to the E3 ubiquitin ligase TRIM25 prevents activation of RIG-I signaling and subsequent IFN induction. Cellular RNA processing is also targeted by NS1, through recognition of cleavage and polyadenylation specificity factor 30 (CPSF30), leading to inhibition of IFN- mRNA processing as well as that of other cellular mRNAs. In addition NS1 binds to and inhibits cellular protein kinase R (PKR), thus blocking an important arm of the IFN system. Many additional proteins have been reported to interact with NS1, either directly or indirectly, which may serve its anti-IFN and additional functions, including the regulation of viral and host gene expression, signaling pathways and viral pathogenesis. Many of these interactions are potential targets for small-molecule intervention. Structural, biochemical and functional studies have resulted in hypotheses for drug discovery approaches that are beginning to bear experimental fruit, such as targeting the dsRNA-NS1 interaction, which could lead to restoration of innate immune function and inhibition of virus replication. This review describes biochemical, cell-based and nucleic acid-based approaches to identifying NS1 antagonists.

A monoclonal antibody binds to threonine 49 in the non-structural 1 protein of influenza A virus and interferes with its ability to modulate viral replication

“…NS1, a well conserved protein, is expressed at very high levels in infected cells (Krug and Etkind, 1973;Palese and Shaw, 2007). Therefore, NS1 protein is a good target for therapeutics development and several small molecules have been found to inhibit NS1 function resulting in reduced viral replication (Engel, 2013;Nayak et al, 2014;Woo et al, 2013). In our previous study, we generated a panel of new monoclonal antibodies (mAbs) against the RNA binding domain of NS1 (NS1(RBD)) .…”

Current and novel antiviral strategies for influenza infection

“…The potential side effects and toxicity of the nucleoside analogs demand further investigation for additional classes of antiviral compounds. In addition to the developing RNP inhibitors that target NP, PB2 cap-binding domain, or the PA endonuclease domain, other promising antiviral agents are being developed that inhibit HA fusion [96,97], HA maturation [98], or NS1 function [99]. While the majority of the novel compounds focused on the inhibitory effect against influenza A virus due to the pandemic potential, research priority should focus on compounds that target conserved domains shared by influenza A and B viruses or between negative-stranded RNA viruses [79 ] as we move forward from in vitro or pre-clinical studies to clinical trials.…”

Identification of Potential Inhibitors against the Human Influenza A Virus Targeting the CPSF30 and RNA Binding Domains of the NS1 Protein: An E-Pharmacophore approach

“…The method incorporates structural and energetic information using the scoring function in Glide XP. 32 As both the targets lack a co-crystallized ligand, in order to generate protein-ligand interaction information for designing the pharmacophore model, the molecules from the glide fragment library which are available for download (http://www.schrodinger.com/ Glide/Fragment-Library) were docked using the XP mode to the respective NS1A binding sites.…”