Verdinexor, a Novel Selective Inhibitor of Nuclear Export, Reduces Influenza A Virus ReplicationIn VitroandIn Vivo

Abstract

Influenza is a global health concern, causing death, morbidity, and economic losses. Chemotherapeutics that target influenza virus are available; however, rapid emergence of drug-resistant strains is common. Therapeutic targeting of host proteins hijacked by influenza virus to facilitate replication is an antiviral strategy to reduce the development of drug resistance. Nuclear export of influenza virus ribonucleoprotein (vRNP) from infected cells has been shown to be mediated by exportin 1 (XPO1) interaction with viral nuclear export protein tethered to vRNP. RNA interference screening has identified XPO1 as a host proinfluenza factor where XPO1 silencing results in reduced influenza virus replication. The Streptomyces metabolite XPO1 inhibitor leptomycin B (LMB) has been shown to limit influenza virus replication in vitro; however, LMB is toxic in vivo, which makes it unsuitable for therapeutic use. In this study, we tested the anti-influenza virus activity of a new class of orally available smallmolecule selective inhibitors of nuclear export, specifically, the XPO1 antagonist KPT-335 (verdinexor). Verdinexor was shown to potently and selectively inhibit vRNP export and effectively inhibited the replication of various influenza virus A and B strains in vitro, including pandemic H1N1 virus, highly pathogenic H5N1 avian influenza virus, and the recently emerged H7N9 strain. In vivo, prophylactic and therapeutic administration of verdinexor protected mice against disease pathology following a challenge with influenza virus A/California/04/09 or A/Philippines/2/82-X79, as well as reduced lung viral loads and proinflammatory cytokine expression, while having minimal toxicity. These studies show that verdinexor acts as a novel anti-influenza virus therapeutic agent. IMPORTANCEAntiviral drugs represent important means of influenza virus control. However, substantial resistance to currently approved influenza therapeutic drugs has developed. New antiviral approaches are required to address drug resistance and reduce the burden of influenza virus-related disease. This study addressed critical preclinical studies for the development of verdinexor (KPT-335) as a novel antiviral drug. Verdinexor blocks progeny influenza virus genome nuclear export, thus effectively inhibiting virus replication. Verdinexor was found to limit the replication of various strains of influenza A and B viruses, including a pandemic H1N1 influenza virus strain, a highly pathogenic H5N1 avian influenza virus strain, and a recently emerging H7N9 influenza virus strain. Importantly, oral verdinexor treatments, given prophylactically or therapeutically, were efficacious in limiting lung virus burdens in influenza virus-infected mice, in addition to limiting lung proinflammatory cytokine expression, pathology, and death. Thus, this study demonstrated that verdinexor is efficacious against influenza virus infection in vitro and in vivo.

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

“…In 2014, the more selective CRM1‐antagonist KPT‐335 (Verdinexor; Fig. C), which is currently in Phase 1 clinical trials, was proven to increase survival in influenza virus‐infected mice …”

Nipah virus matrix protein: expert hacker of cellular machines

“…Experiments using a relatively toxic SINE (LMB) have demonstrated proof-of-concept for inhibition of NiV-M function [66], paving the way for possible repurposing of the numerous novel SINE compounds with vastly improved toxicity profiles that are currently showing promise at various stages of cancer clinical trials [121]. Interestingly, repurposing of SINE compounds as antiviral drugs has already been investigated for IAV [122] and HIV-1 [123]. …”

Targeting the pro‐inflammatory factor CCL2 (MCP‐1) with Bindarit for influenza A (H7N9) treatment

“…The sections were evaluated using light microscopy. A histological score for each lung was determined according to the following criteria: 0=no lung abnormality; 1=<10% of airways inflamed; 2=10–30% of airways inflamed; 3=30–50% of airways inflamed and 4=>50% of airways inflamed 50 . The slides were evaluated by a pathologist without prior knowledge of the infection and treatment status.…”