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Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir

Jiang et al., Nature Communications, doi:10.1038/s41467-023-42102-y
Oct 2023  
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In Vitro and mouse study showing the development and preclinical evaluation of the SARS-CoV-2 3C-like protease (3CLpro) inhibitor simnotrelvir (SSD8432, SIM0417, part of xiannuoxin) as an orally bioavailable COVID-19 therapeutic agent. Structure-based optimization of the HCV protease inhibitor boceprevir led to identification of simnotrelvir, which covalently inhibits 3CLpro from SARS-CoV-2 and other coronaviruses. Simnotrelvir demonstrated potent antiviral activity against SARS-CoV-2 variants in enzymatic and cell-based assays and showed favorable pharmacokinetics, safety profiles, and robust oral efficacy in a mouse model of SARS-CoV-2 delta infection, significantly reducing lung viral loads and eliminating virus from brains.
2 preclinical studies support the efficacy of xiannuoxin for COVID-19:
Jiang et al., 13 Oct 2023, China, peer-reviewed, 22 authors. Contact: ycxu@simm.ac.cn, renhong.tang@simceregroup.com, zhangleike@wh.iov.cn, shenjingshan@simm.ac.cn.
This PaperXiannuoxinAll
Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir
Xiangrui Jiang, Haixia Su, Weijuan Shang, Feng Zhou, Yan Zhang, Wenfeng Zhao, Qiumeng Zhang, Hang Xie, Lei Jiang, Tianqing Nie, Feipu Yang, Muya Xiong, Xiaoxing Huang, Minjun Li, Ping Chen, Shaoping Peng, Gengfu Xiao, Hualiang Jiang, Renhong Tang, Leike Zhang, Jingshan Shen, Yechun Xu
Nature Communications, doi:10.1038/s41467-023-42102-y
The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CL pro ) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CL pro with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CL pro inhibitor but has high selectivity. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses. The catastrophic coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants has resulted in an unbearable number of infections and deaths worldwide, and posed an unprecedented threat to global public health and economies. Thus, great efforts have been devoted to developing vaccines as well as antiviral agents for the treatment and prevention of COVID-19, but the clinically significant therapeutic options for COVID-19 are limited. According to therapeutic strategies against other viruses, such as HCV and HIV, orally effective small molecule drugs targeting viral proteins that are essential for virus replication have been particularly pursued to combat the ongoing pandemic and future SARS-like zoonotic coronavirus outbreaks.
Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Data availability The atomic coordinates and structure factors have been deposited into the Protein Data Bank with accession codes 8IFP (SARS-CoV-2 3 CL pro in complex with compound 1), 8IFQ (SARS-CoV-2 3CL pro in complex with compound 2), 8IFR (SARS-CoV-2 3CL pro in complex with compound 3), 8IFS (SARS-CoV-2 3CL pro in complex with compound 7), 8IFT (SARS-CoV-2 3CL pro in complex with compound 10), 8IGX (SARS-CoV-2 3CL pro in complex with simnotrelvir), and 8IGY (SARS-CoV-2 3CL pro in complex with nirmatrelvir). The structure of SARS-CoV-2 3CL pro in complex with boceprevir (PDB code: 6XQU) was obtained from Protein Data Bank. The cDNA of 3CL pro s of SARS-CoV-2 (Gen-Bank: MN908947.3), SARS-CoV (Gen-Bank: AAP13442.1), MERS-CoV (Gen-Bank: MT387202.1), H229E-CoV (Gen-Bank: AF304460.1), HKU1-CoV (Gen-Bank: AY597011.2), NL63-CoV (Gen-Bank: AY567487.2), and OC43-CoV (Gen-Bank: AY903459.1) were obtained from Genbank [https://https.ncbi.nlm.nih.gov/genbank/]. Source data are provided with this paper. All the raw data generated in this study are provided in the Source Data file. Source data are provided with this paper. Author contributions Y.X., X.J., and J.S. conceived and design the project. Y.X., X.J., J.S., H.J., L.Z., H.S., F.Z., and R.T. designed the experiments; Y.X., X.J., J.S., H.S., and M.X. performed the drug design; X.J., J.S.,..
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Drug Discov. 11, 909–922 ' '(2012).', 'volume': '11', 'year': '2012'}, { 'DOI': '10.1126/science.abf1611', 'author': 'J Qiao', 'doi-asserted-by': 'publisher', 'first-page': '1374', 'journal-title': 'Science', 'key': '42102_CR20', 'unstructured': 'Qiao, J. et al. SARS-CoV-2 M(pro) inhibitors with antiviral activity in ' 'a transgenic mouse model. Science 371, 1374–1378 (2021).', 'volume': '371', 'year': '2021'}, { 'DOI': '10.1038/s41467-022-29915-z', 'author': 'DW Kneller', 'doi-asserted-by': 'publisher', 'journal-title': 'Nat. Commun.', 'key': '42102_CR21', 'unstructured': 'Kneller, D. W. et al. Covalent narlaprevir- and boceprevir-derived ' 'hybrid inhibitors of SARS-CoV-2 main protease. Nat. Commun. 13, 2268 ' '(2022).', 'volume': '13', 'year': '2022'}, { 'DOI': '10.1021/acscatal.8b05051', 'author': 'YH Wang', 'doi-asserted-by': 'publisher', 'first-page': '2292', 'journal-title': 'Acs Catal.', 'key': '42102_CR22', 'unstructured': 'Wang, Y. H. et al. Covalent inhibition mechanism of antidiabetic ' 'drugs-vildagliptin vs saxagliptin. Acs Catal. 9, 2292–2302 (2019).', 'volume': '9', 'year': '2019'}, { 'DOI': '10.1038/s41573-022-00542-z', 'author': 'L Boike', 'doi-asserted-by': 'publisher', 'first-page': '881', 'journal-title': 'Nat. Rev. Drug Discov.', 'key': '42102_CR23', 'unstructured': 'Boike, L., Henning, N. J. & Nomura, D. K. Advances in covalent drug ' 'discovery. Nat. Rev. Drug Discov. 21, 881–898 (2022).', 'volume': '21', 'year': '2022'}, { 'DOI': '10.1016/j.jbbm.2005.12.008', 'author': 'F van den Ent', 'doi-asserted-by': 'publisher', 'first-page': '67', 'journal-title': 'J. Biochem. Biophys. Methods', 'key': '42102_CR24', 'unstructured': 'van den Ent, F. & Lowe, J. RF cloning: a restriction-free method for ' 'inserting target genes into plasmids. J. Biochem. Biophys. 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D 58, ' '1948–1954 (2002).', 'volume': '58', 'year': '2002'}], 'reference-count': 31, 'references-count': 31, 'relation': {}, 'resource': {'primary': {'URL': 'https://www.nature.com/articles/s41467-023-42102-y'}}, 'score': 1, 'short-title': [], 'source': 'Crossref', 'subject': [ 'General Physics and Astronomy', 'General Biochemistry, Genetics and Molecular Biology', 'General Chemistry', 'Multidisciplinary'], 'subtitle': [], 'title': 'Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease ' 'inhibitor simnotrelvir', 'type': 'journal-article', 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'volume': '14'}
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