2. Academic Validation
  3. USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice

USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice

  • Sci Transl Med. 2023 Dec 6;15(725):eadh7668. doi: 10.1126/scitranslmed.adh7668.
Fabin Dang 1,  Lei Bai 2,  Jiazhen Dong 2,  Xiaoping Hu 3,  Jingchao Wang 1,  Joao A Paulo 4,  Yan Xiong 3,  Xiaowei Liang 2,  Yishuang Sun 5,  Yuncai Chen 2,  Ming Guo 2,  Xin Wang 2,  Zhixiang Huang 2,  Hiroyuki Inuzuka 1,  Li Chen 1,  Chen Chu 6,  Jianping Liu 7,  Tao Zhang 1,  Abdol-Hossein Rezaeian 1,  Jing Liu 1,  Husnu Ümit Kaniskan 3,  Bo Zhong 5 8,  Jinfang Zhang 5 8,  Michael Letko 9,  Jian Jin 3,  Ke Lan 2 5 8,  Wenyi Wei 1
Affiliations

Affiliations

  • 1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • 2 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 3 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 4 Department of Cell Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA.
  • 5 Medical Research Institute, Wuhan University, Wuhan 430071, China.
  • 6 Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 7 State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
  • 8 TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430072, China.
  • 9 Paul G. Allen School for Global Health, Washington State University, Pullman, WA 99163 USA.
PMID: 38055802 DOI: 10.1126/scitranslmed.adh7668
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.

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