SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

Source: ScienceNOW - March 25, 2021 Category: Science Authors: Qiao, J., Li, Y.-S., Zeng, R., Liu, F.-L., Luo, R.-H., Huang, C., Wang, Y.-F., Zhang, J., Quan, B., Shen, C., Mao, X., Liu, X., Sun, W., Yang, W., Ni, X., Wang, K., Xu, L., Duan, Z.-L., Zou, Q.-C., Zhang, H.-L., Qu, W., Long, Y.-H.-P., Li, M.-H., Yang, R. Tags: Microbiology, Virology reports Source Type: news