Respiratory syncytial virus (RSV) infection accounts for substantial worldwide morbidity and some mortality among infants and elderly and those with cardiac or pulmonary issues. The standard of care for RSV-infected patients is limited to supportive therapy, and there is no safe and efficacious RSV vaccine. There is one approved anti-RSV drug, i.e. inhaled ribavirin, but its effectiveness is questionable and it is difficult to administer. The long-term goal of this project is to develop a novel class of RSV anti-viral therapeutics that target the host protein nuclear export machinery (Exportin-1/XPO1) that is co-opted by RSV for its replication. A prototypical inhibitor of XPO1, leptomycin B (LMB) has been shown in vitro to block RSV replication. However, LMB failed Phase 1 trials due to in vivo toxicity with anorexia and malaise. Karyopharm Therapeutics has developed first-in-class selective inhibitors of nuclear export which block XPO1-directed nuclear export. One compound, KPT-335 (Verdinexor), is in a late-phase development for treatment of canine malignancy. We hypothesize that KPT-335 will safely and effectively block RSV replication by inhibiting nuclear export of RSV M protein. As the nuclear export signal (NES) of the RSV M protein is conserved among strains, we propose therapeutic and prophylactic studies to assess KPT-335 efficacy against different RSV group A and B strains, and determine the mechanism of action against RSV by evaluating M protein localization and XPO1 binding to the M protein. The overall goal of these studies proposed is to achieve a critical milestone and establish in vitro anti-RSV efficacy of KPT-335 as the basis to move this important drug forward for prospective in vivo studies.
RSV is the most significant cause of serious lower respiratory tract infection in infants and young children worldwide. There is currently no vaccine and antiviral therapy (ribavirin) has no/limited efficacy against the disease. New anti-viral approaches are required to reduce the burden of RSV-related disease. This proposal is aimed to address critical in vitro studies needed for the development KPT-335 as a novel RSV anti-viral drug.
| Pickens, Jennifer A; Tripp, Ralph A (2018) Verdinexor Targeting of CRM1 is a Promising Therapeutic Approach against RSV and Influenza Viruses. Viruses 10: |
