Qiao J, Li YS, Zeng R, Liu FL, Luo RH, Huang C, Wang YF, Zhang J, Quan B, Shen C, Mao X, Liu X, Sun W, Yang W, Ni X, Wang K, Xu L, Duan ZL, Zou QC, Zhang HL, Qu W, Long YH, Li MH, Yang RC, Liu X, You J, Zhou Y, Yao R, Li WP, Liu JM, Chen P, Liu Y, Lin GF, Yang X, Zou J, Li L, Hu Y, Lu GW, Li WM, Wei YQ, Zheng YT, Lei J, Yang S

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 ...

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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.

Date: Mar. 26, 2021

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