Respiratory syncytial virus (RSV) is an enveloped, single-stranded, negative-sense RNA virus. It belongs to the Pneumovirinae subfamily of Paramyxoviridae. Furthermore, this kind of virus infects the respiratory tract of humans and causes severe diseases.
Sisunatovir is an orally available inhibitor of the RSV fusion (RSV-F) protein.
Sisunatovir i.v administration exhibits a good PK profile. It shows a T1/2, CL, Vdss values of 1.78 hours, 131.8 ml/min/kg, 21.97L/kg, respectively. After an oral administration, Sisunatovir shows a T1/2 of 9.92 hours and 12.0 hours, respectively after a dosage of 10 mg/kg and 50 mg/kg. Additionally, the Tmax and Cmax are 2.96 and 5.9 at 10 mg/kg and 50 mg/kg, respectively.
In balb-c mouse efficacy, Sisunatovir exhibits a good efficacy in vivo. Use Sisunatovir lung virus titres as a control, 1 mg/kg Sisunatovir approximately reduces 80% virus titrers when it compares to the control. Additionally, 10 mg/kg Sisunatovir approximately reduces 90% virus titres.
In the human airway epithelial model, the in vitro system displays the morphologic and phenotypic characteristics of in vivo model. Sisunatovir applies to the basolateral surface with the virus to replication infection and systemic treatment. As a result, Sisunatovir results in a dose-dependent reduction in vitro.
Sisunatovir inhibits RSV A and B types with IC50 values both <10 nM.
In a cell cytotoxicity assay, Sisunatovir inhibits BJ, H4-II-E-C3, HUV-EC-C, MRC-5, and Neuro-2a with IC50 values of 16 μM, 14μM, 13 μM, 13 μM, and 15 μM, respectively. Additionally, Sisunatovir inhibits hek-293, hepG2, HK2, Jurkat cells with IC50 values of 30 μM,31 μM, >50 μM, 30 μM and 26 μM, respectively.
Besides, in the in vitro resistance generation, a single mutation D489Y in RSV F protein for Sisunatovir resistant virus. The mutant shows cross-resistance with GS-5806. GS-5806 is an orally bioavailable RSV fusion inhibitor with a mean EC50 value of 0.43 nM. It shows a larger EC50 shift than Sisunatovir against all resistant variants.
In summary, Sisunatovir, as a potent inhibitor of the RSV fusion (RSV-F) protein. It exhibits potent efficacy against a panel of clinical isolates of RSV-A and RSV-B viruses, with IC50s of 1.4 nM and 1.0 nM, respectively.