Kim Jinwoo, Jung Yu Kyoung, Kim Chonsaeng, Shin Jin Soo, Scheers Els, Lee Joo-Youn, Han Soo Bong, Lee Chong-Kyo, Neyts Johan, Ha Jae-Du, Jung Young-Sik
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology , 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea.
Department of Medicinal Chemistry and Pharmacology, University of Science and Technology , 217 Gajeongro, Yuseong, Daejeon 34113, Republic of Korea.
J Med Chem. 2017 Jul 13;60(13):5472-5492. doi: 10.1021/acs.jmedchem.7b00175. Epub 2017 Jun 15.
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 EC 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.
人鼻病毒（hRVs）是普通感冒的主要致病病原体，且与哮喘的恶化有关。hRV血清型的广泛多样性使鼻病毒复制抑制剂的研发变得复杂。在当前的研究中，我们开发了一系列新型苯并噻吩衍生物及其类似物（6 - 8），它们能有效抑制hRV - A和hRV - B毒株的复制。化合物6g抑制hRV - B14、A21和A71的复制，其各自的EC值分别为0.083、0.078和0.015 μM。针对hRV - B14和hRV - A16的添加时间研究结果以及对hRV - B14的抗性突变分析表明，6g在病毒复制过程的早期起作用，与病毒衣壳蛋白相互作用。分子对接研究表明，6g具有与普来可那立相似的衣壳结合模式。最后，6的衍生物对脊髓灰质炎病毒3（PV3）的复制也显示出显著抑制作用，这意味着它们对其他肠道病毒种类具有潜在的抑制活性。
