Abstract
Infectious diseases are a major global concern and despite major advancements in medical research, still cause significant morbidity and mortality. Progress in antiviral therapy is particularly hindered by appearance of mutants capable of overcoming the effects of drugs targeting viral components. Alternatively, development of drugs targeting host proteins essential for completion of viral lifecycle holds potential as a viable strategy for antiviral therapy. Nucleocytoplasmic trafficking pathways in particular are involved in several pathological conditions including cancer and viral infections, where hijacking or alteration of function of key transporter proteins, such as Chromosome Region Maintenance1 (CRM1) is observed. Overexpression of CRM1-mediated nuclear export is evident in several solid and hematological malignancies. Interestingly, CRM1-mediated nuclear export of viral components is crucial in various stages of the viral lifecycle and assembly. This review summarizes the role of CRM1 in cancer and selected viruses. Leptomycin B (LMB) is the prototypical inhibitor of CRM1 potent against various cancer cell lines overexpressing CRM1 and in limiting viral infections at nanomolar concentrations in vitro. However, the irreversible shutdown of nuclear export results in high cytotoxicity and limited efficacy in vivo. This has prompted search for synthetic and natural CRM1 inhibitors that can potentially be developed as broadly active antivirals, some of which are summarized in this review.
Highlights
OverviewDespite concerted effort, spearheaded by the World Health Organization (WHO), the number of deaths caused by infectious diseases is falling slowly
The electrophilic α,β-unsaturated carbonyl group of piperlongumine has been shown to covalently modify Cys528 of Chromosome Region Maintenance1 (CRM1) in a Michael addition manner and inactivate CRM1-mediated protein export (Niu et al, 2015). This suggests piperlongumine-induced suppression of constitutive NFκB, Akt/mammalian target of rapamycin and MAPK signal pathways and cytotoxicity in tumorigenic cells demonstrated in several studies could be explained by its interference with CRM1-mediated export
CRM1 is a conserved and well characterized nuclear exporter that binds to protein/mRNA cargoes tagged with an nuclear export sequences (NESs) motif
Summary
OverviewDespite concerted effort, spearheaded by the World Health Organization (WHO), the number of deaths caused by infectious diseases is falling slowly. Interruption of CRM1-mediated export results in changes in virion protein expression, virion replication, incomplete viral assembly, reduced infectivity, and improved antiviral host immune responses (Elton et al, 2001; Pasdeloup et al, 2005; Cao and Liu, 2007; Sanchez et al, 2007; Ghildyal et al, 2009; Cao et al, 2012; Liu et al, 2012; Nakano and Watanabe, 2016).
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