posted on 2022-02-02, 12:36authored byWenyue Cao, Chia-Chuan Dean Cho, Zhi Zachary Geng, Namir Shaabani, Xinyu R. Ma, Erol C. Vatansever, Yugendar R. Alugubelli, Yuying Ma, Sankar P. Chaki, William H. Ellenburg, Kai S. Yang, Yuchen Qiao, Robert Allen, Benjamin W. Neuman, Henry Ji, Shiqing Xu, Wenshe Ray Liu
As an essential enzyme
of SARS-CoV-2, main protease (MPro) triggers acute toxicity
to its human cell host, an effect that
can be alleviated by an MPro inhibitor. Using this toxicity
alleviation, we developed an effective method that allows a bulk analysis
of the cellular potency of MPro inhibitors. This novel
assay is advantageous over an antiviral assay in providing precise
cellular MPro inhibition information to assess an MPro inhibitor. We used this assay to analyze 30 known MPro inhibitors. Contrary to their strong antiviral effects
and up to 10 μM, 11a, calpain inhibitor II, calpain XII, ebselen,
bepridil, chloroquine, and hydroxychloroquine showed relatively weak
to undetectable cellular MPro inhibition potency implicating
their roles in interfering with key steps other than just the MPro catalysis in the SARS-CoV-2 life cycle. Our results also
revealed that MPI5, MPI6, MPI7, and MPI8 have high cellular and antiviral
potency. As the one with the highest cellular and antiviral potency
among all tested compounds, MPI8 has a remarkable cellular MPro inhibition IC50 value of 31 nM that matches closely to
its strong antiviral effect with an EC50 value of 30 nM.
Therefore, we cautiously suggest exploring MPI8 further for COVID-19
preclinical tests.