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Inducible and Reversible Dominant-negative DN Protein Inhibition
Published on: January 7, 2019
SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model
Jingxin Qiao1, Yue-Shan Li1, Rui Zeng1
1State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Abstract:
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.
Insights
New bicycloproline-containing inhibitors show potent activity against SARS-CoV-2 main protease (Mpro). Two compounds demonstrated significant antiviral effects in cell and mouse models, offering promising therapeutic potential for COVID-19 treatment.
Area of Science:
- Medicinal Chemistry
- Virology
- Structural Biology
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, remains a global health concern.
- The SARS-CoV-2 main protease (Mpro) is crucial for viral replication and a key drug target.
Purpose of the Study:
- To design and synthesize novel Mpro inhibitors.
- To evaluate their in vitro, cellular, and in vivo antiviral efficacy.
Main Methods:
- Synthesis of 32 bicycloproline-containing compounds derived from boceprevir and telaprevir.
- In vitro enzyme inhibition assays and Mpro-ligand cocrystallography.
- Cell-based antiviral assays and a transgenic mouse model of SARS-CoV-2 infection.
- Pharmacokinetic and safety assessments in rats.
Main Results:
- All synthesized compounds inhibited SARS-CoV-2 Mpro in vitro, with IC50 values from 7.6 to 748.5 nM.
- Cocrystal structure elucidated the binding mode of potent inhibitor MI-23.
- Compounds MI-09 and MI-30 exhibited strong antiviral activity in cell cultures.
- MI-09 and MI-30 significantly reduced viral load and lung lesions in infected mice.
- These compounds demonstrated favorable pharmacokinetic profiles and safety in rats.
Conclusions:
- Novel bicycloproline-based Mpro inhibitors were successfully developed.
- MI-09 and MI-30 show significant potential as therapeutic agents for COVID-19.
- Further development of these compounds is warranted for clinical application.
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