Post-infection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection

Dampalla, C.; Zheng, J.; Perera, K.; Wong, L. Y. R.; Meyerholz, D.; Nguyen, H.; Kashipathy, M.; Battaile, K.; Lovell, S.; Kim, Y.; Perlman, S.; Groutas, W.; Chang, K.-O.

doi:10.1101/2021.02.05.429937

bioRxiv · 10.1101/2021.02.05.429937

Post-infection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection

Dampalla, C.·Zheng, J.·Perera, K.·Wong, L. Y. R.·Meyerholz, D.·Nguyen, H.·Kashipathy, M.·Battaile, K.·Lovell, S.·Kim, Y.·Perlman, S.·Groutas, W.·Chang, K.-O.

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and was proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 hr post infection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2-treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.

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Dampalla, C., Zheng, J., Perera, K., Wong, L. Y. R., Meyerholz, D., Nguyen, H., Kashipathy, M., Battaile, K., Lovell, S., Kim, Y., Perlman, S., Groutas, W., Chang, K.-O.. 2021-02-05. Post-infection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection. https://doi.org/10.1101/2021.02.05.429937

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