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- Title
USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice.
- Authors
Dang, Fabin; Bai, Lei; Dong, Jiazhen; Hu, Xiaoping; Wang, Jingchao; Paulo, Joao A.; Xiong, Yan; Liang, Xiaowei; Sun, Yishuang; Chen, Yuncai; Guo, Ming; Wang, Xin; Huang, Zhixiang; Inuzuka, Hiroyuki; Chen, Li; Chu, Chen; Liu, Jianping; Zhang, Tao; Rezaeian, Abdol-Hossein; Liu, Jing
- Abstract
Targeting angiotensin-converting enzyme 2 (ACE2) represents a promising and effective approach to combat not only the COVID-19 pandemic but also potential future pandemics arising from coronaviruses that depend on ACE2 for infection. Here, we report ubiquitin specific peptidase 2 (USP2) as a host-directed antiviral target; we further describe the development of MS102, an orally available USP2 inhibitor with viable antiviral activity against ACE2-dependent coronaviruses. Mechanistically, USP2 serves as a physiological deubiquitinase of ACE2, and targeted inhibition with specific small-molecule inhibitor ML364 leads to a marked and reversible reduction in ACE2 protein abundance, thereby blocking various ACE2-dependent coronaviruses tested. Using human ACE2 transgenic mouse models, we further demonstrate that ML364 efficiently controls disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as evidenced by reduced viral loads and ameliorated lung inflammation. Furthermore, we improved the in vivo performance of ML364 in terms of both pharmacokinetics and antiviral activity. The resulting lead compound, MS102, holds promise as an oral therapeutic option for treating infections with coronaviruses that are reliant on ACE2. Editor's summary: Therapeutics such as monoclonal antibodies and antivirals have changed the course of the SARS-CoV-2 pandemic. However, these therapies are directed at the virus itself, which can result in development of resistant viral strains. One promising strategy would be to direct therapies toward angiotensin-converting enzyme 2 (ACE2); without ACE2 expression, SARS-CoV-2 cannot enter a cell to replicate and propagate infection. Here, Dang et al. identified ubiquitin specific peptidase 2 (USP2) as a deubiquitinase that stabilizes ACE2 protein. Inhibition of USP2 with a small molecule, ML364, decreased ACE2 protein abundance and prevented infection with multiple SARS-CoV-2 variants in vitro. Furthermore, oral treatment with an optimized USP2 inhibitor, MS102, conferred protection against SARS-CoV-2 in multiple murine models, highlighting the potential of this host-directed therapeutic. —Courtney Malo
- Subjects
DEUBIQUITINATING enzymes; VIRAL shedding
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 725, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adh7668