A Novel Series of Highly Potent Small Molecule Inhibitors of Rhinovirus Replication

Human
rhinoviruses (hRVs) are the main causative pathogen for common
colds and are associated with the exacerbation of asthma. The wide
variety in hRV serotypes has complicated the development of rhinovirus
replication inhibitors. In the current investigation, we developed
a novel series of benzothiophene derivatives and their analogues (6–8) that potently inhibit the replication
of both hRV-A and hRV-B strains. Compound 6g inhibited
the replication of hRV-B14, A21, and A71, with respective EC50 values of 0.083, 0.078, and 0.015 μM. The results of a time-of-addition
study against hRV-B14 and hRV-A16 and resistant mutation analysis
on hRV-B14 implied that 6g acts at the early stage of
the viral replication process, interacting with viral capsid protein.
A molecular docking study suggested that 6g has a capsid-binding
mode similar to that of pleconaril. Finally, derivatives of 6 also displayed significant inhibition against poliovirus
3 (PV3) replication, implying their potential inhibitory activities
against other enterovirus species.