3 years ago

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

A Novel Series of Highly Potent Small Molecule Inhibitors of Rhinovirus Replication
Joo-Youn Lee, Young-Sik Jung, Chong-Kyo Lee, Yu Kyoung Jung, Jinwoo Kim, Soo Bong Han, Jin Soo Shin, Jae-Du Ha, Johan Neyts, Els Scheers, Chonsaeng Kim
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 (68) 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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00175

DOI: 10.1021/acs.jmedchem.7b00175

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