Abstract
Two primary causes of respiratory tract infections are respiratory syncytial virus (RSV) and influenza viruses, both of which remain major public health concerns. There are a limited number of antiviral drugs available for the treatment of RSV and influenza, each having limited effectiveness and each driving selective pressure for the emergence of drug-resistant viruses. Novel broad-spectrum antivirals are needed to circumvent problems with current disease intervention strategies, while improving the cytokine-induced immunopathology associated with RSV and influenza infections. In this review, we examine the use of Verdinexor (KPT-335, a novel orally bioavailable drug that functions as a selective inhibitor of nuclear export, SINE), as an antiviral with multifaceted therapeutic potential. KPT-335 works to (1) block CRM1 (i.e., Chromosome Region Maintenance 1; exportin 1 or XPO1) mediated export of viral proteins critical for RSV and influenza pathogenesis; and (2) repress nuclear factor κB (NF-κB) activation, thus reducing cytokine production and eliminating virus-associated immunopathology. The repurposing of SINE compounds as antivirals shows promise not only against RSV and influenza virus but also against other viruses that exploit the nucleus as part of their viral life cycle.
Highlights
Influenza A virus (IAV) and respiratory syncytial virus (RSV) are two leading causes of viral respiratory tract illnesses, resulting in considerable mortality and morbidity
Antiviral therapeutics generally target viral proteins needed for replication and many have proven to be ineffective at preventing influenza- and RSV-associated diseases due to features associated with the emergence of drug resistance
For the influenza virus and RSV, the TLR3 and TLR7/8 responses are involved in the detection of regulate cytokine and chemokine expression, including nuclear factor κB (NF-κB), interferon regulatory factors (IRFs) and activating transcription factor 2 (ATF-2)/cJun [143,144,147]
Summary
Influenza A virus (IAV) and respiratory syncytial virus (RSV) are two leading causes of viral respiratory tract illnesses, resulting in considerable mortality and morbidity. RSV infections typically result in mild upper respiratory tract illness, but in severe cases, can cause bronchiolitis and pneumonia requiring hospitalization [8]. Antiviral therapeutics generally target viral proteins needed for replication and many have proven to be ineffective at preventing influenza- and RSV-associated diseases due to features associated with the emergence of drug resistance. To avoid these issues, research efforts have focused on identifying and evaluating new antiviral drugs that target cellular factors and pathways hijacked by the virus used in replication, rather than focus on a viral component that may readily change under the selective pressure of the drug and/or immune system. Region Maintenance 1; exportin 1 or XPO1) dependent export pathway as a broad-spectrum antiviral therapeutic strategy against the influenza virus and RSV
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