CRM1 Inhibitors for Antiviral Therapy

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.

Keywords: CRM1; CRM1 in cancer; CRM1 inhibitors; CRM1-mediated export of viral proteins; CRM1-mediated nuclear export.

Figure 1

Nuclear export. Nuclear export is initiated by the recognition of an NES-carrying cargo by CRM1 and formation of a tricomplex with RanGTP. This is followed by sequential docking and undocking events at the NPC. After translocation into the cytoplasm the tricomplex is dissociated by the hydrolysis of RanGTP to RanGDP by RanGAP. The released CRM1 protein returns to the nucleus and repeats the process.

Figure 2

Function of CRM1-mediated export and its significance in cancer. The illustration summarizes some of the key proteins, including tumor suppressor proteins, cell cycle regulators, mediators of cell proliferation and apoptosis, proteins involved in maintenance of chromosomal and nuclear structures and others, regulated by CRM1-mediated nuclear export and their role in several solid and/or hematological malignancies. Abbreviations. APC, Adenomatous Polyposis Coli; ATF2, Activating transcription factor 2; BCR-ABL, Breakpoint Cluster Region/Abelson murine leukemia viral oncogene homolog 1 Bok, Bcl-2 related ovarian killer; BRCA1-Early Onset Breast Cancer 1; CIP2A, Cancerous Inhibitor of PP2A; ERα, Estrogen Receptor; ERK, Extracellular signal-Regulated Kinases; FOXO, Forkhead family of transcription factors; HMGB1, High Mobility Group Box 1; Hsp90, Heat Shock Protein 90; RASSF2, Ras association (RalGDS/AF-6) domain family member 2; RB, Retinoblastoma; RUNX3, Runt-related transcription factor 3; Tob, Transducer of ErbB-2.

Figure 3

CRM1-inhibition by Leptomycin B. Leptomycin B binds to CRM1 at Cys528 residing in its NES-binding groove and inhibits the binding of the cargo to CRM1.