Viral replication

Genetically modified mouse

Virology

Chemistry

Coronavirus

Biochemistry

Vero cell

Enzyme

Infectious disease (medical specialty)

Virus

Disease

Ribavirin

Coronavirus disease 2019 (COVID-19)

Biology

Gene

Protease

Boceprevir

Telaprevir

Transgene

Pathology

Pharmacology

In vitro

Hepatitis C virus

Medicine

Science

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.

SARS-CoV-2 M <sup>pro</sup> inhibitors with antiviral activity in a transgenic mouse model

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

SARS-CoV-2 M ^pro inhibitors with antiviral activity in a transgenic mouse model