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

{ 'indexed': {'date-parts': [[2024, 2, 22]], 'date-time': '2024-02-22T10:04:41Z', 'timestamp': 1708596281697}, 'reference-count': 31, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2023, 10, 13]], 'date-time': '2023-10-13T00:00:00Z', 'timestamp': 1697155200000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2023, 10, 13]], 'date-time': '2023-10-13T00:00:00Z', 'timestamp': 1697155200000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'funder': [ { 'DOI': '10.13039/100012543', 'name': 'Shanghai Science and Technology Development Foundation', 'doi-asserted-by': 'publisher', 'award': ['No. 22YF1457300']}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'abstract': '<jats:title>Abstract</jats:title><jats:p>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<jats:sup>pro</jats:sup>) 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<jats:sup>pro</jats:sup> with an ' 'enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that ' 'simnotrelvir is a potent pan-CoV\xa03CL<jats:sup>pro</jats:sup> 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.</jats:p>', 'DOI': '10.1038/s41467-023-42102-y', 'type': 'journal-article', 'created': { 'date-parts': [[2023, 10, 13]], 'date-time': '2023-10-13T18:03:06Z', 'timestamp': 1697220186000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 8, 'title': 'Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease ' 'inhibitor simnotrelvir', 'prefix': '10.1038', 'volume': '14', 'author': [ {'given': 'Xiangrui', 'family': 'Jiang', 'sequence': 'first', 'affiliation': []}, {'given': 'Haixia', 'family': 'Su', 'sequence': 'additional', 'affiliation': []}, {'given': 'Weijuan', 'family': 'Shang', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0009-0007-3050-6239', 'authenticated-orcid': False, 'given': 'Feng', 'family': 'Zhou', 'sequence': 'additional', 'affiliation': []}, {'given': 'Yan', 'family': 'Zhang', 'sequence': 'additional', 'affiliation': []}, {'given': 'Wenfeng', 'family': 'Zhao', 'sequence': 'additional', 'affiliation': []}, {'given': 'Qiumeng', 'family': 'Zhang', 'sequence': 'additional', 'affiliation': []}, {'given': 'Hang', 'family': 'Xie', 'sequence': 'additional', 'affiliation': []}, {'given': 'Lei', 'family': 'Jiang', 'sequence': 'additional', 'affiliation': []}, {'given': 'Tianqing', 'family': 'Nie', 'sequence': 'additional', 'affiliation': []}, {'given': 'Feipu', 'family': 'Yang', 'sequence': 'additional', 'affiliation': []}, {'given': 'Muya', 'family': 'Xiong', 'sequence': 'additional', 'affiliation': []}, {'given': 'Xiaoxing', 'family': 'Huang', 'sequence': 'additional', 'affiliation': []}, {'given': 'Minjun', 'family': 'Li', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ping', 'family': 'Chen', 'sequence': 'additional', 'affiliation': []}, {'given': 'Shaoping', 'family': 'Peng', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-9401-235X', 'authenticated-orcid': False, 'given': 'Gengfu', 'family': 'Xiao', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0003-0656-6315', 'authenticated-orcid': False, 'given': 'Hualiang', 'family': 'Jiang', 'sequence': 'additional', 'affiliation': []}, {'given': 'Renhong', 'family': 'Tang', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-2593-2571', 'authenticated-orcid': False, 'given': 'Leike', 'family': 'Zhang', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-9679-9934', 'authenticated-orcid': False, 'given': 'Jingshan', 'family': 'Shen', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-1581-6155', 'authenticated-orcid': False, 'given': 'Yechun', 'family': 'Xu', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2023, 10, 13]]}, 'reference': [ { 'key': '42102_CR1', 'first-page': '151', 'volume': '1', 'author': 'H Su', 'year': '2021', 'unstructured': 'Su, H., Xu, Y. & Jiang, H. Drug discovery and development targeting the ' 'life cycle of SARS-CoV-2. Fund. Res. 1, 151–165 (2021).', 'journal-title': 'Fund. Res.'}, { 'key': '42102_CR2', 'doi-asserted-by': 'publisher', 'first-page': '1965', 'DOI': '10.1002/med.21783', 'volume': '41', 'author': 'M Xiong', 'year': '2021', 'unstructured': 'Xiong, M. et al. What coronavirus 3C-like protease tells us: from ' 'structure, substrate selectivity, to inhibitor design. Med. Res. Rev. ' '41, 1965–1998 (2021).', 'journal-title': 'Med. Res. Rev.'}, { 'key': '42102_CR3', 'doi-asserted-by': 'publisher', 'first-page': '1014', 'DOI': '10.1126/science.abd0831', 'volume': '369', 'author': 'A Baum', 'year': '2020', 'unstructured': 'Baum, A. et al. Antibody cocktail to SARS-CoV-2 spike protein prevents ' 'rapid mutational escape seen with individual antibodies. Science 369, ' '1014–1018 (2020).', 'journal-title': 'Science'}, { 'key': '42102_CR4', 'doi-asserted-by': 'publisher', 'first-page': '1586', 'DOI': '10.1126/science.abl4784', 'volume': '374', 'author': 'DR Owen', 'year': '2021', 'unstructured': 'Owen, D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate ' 'for the treatment of COVID-19. Science 374, 1586–1593 (2021).', 'journal-title': 'Science'}, { 'key': '42102_CR5', 'doi-asserted-by': 'publisher', 'first-page': '6496', 'DOI': '10.1021/acs.jmedchem.2c00624', 'volume': '65', 'author': 'JDA Tyndall', 'year': '2022', 'unstructured': 'Tyndall, J. D. A. S-217622, a 3CL protease inhibitor and clinical ' 'candidate for SARS-CoV-2. J. Med. Chem. 65, 6496–6498 (2022).', 'journal-title': 'J. Med. Chem.'}, { 'key': '42102_CR6', 'doi-asserted-by': 'publisher', 'first-page': '1331', 'DOI': '10.1126/science.abb4489', 'volume': '368', 'author': 'W Dai', 'year': '2020', 'unstructured': 'Dai, W. et al. Structure-based design of antiviral drug candidates ' 'targeting the SARS-CoV-2 main protease. Science 368, 1331–1335 (2020).', 'journal-title': 'Science'}, { 'key': '42102_CR7', 'doi-asserted-by': 'publisher', 'first-page': '50', 'DOI': '10.1021/ar700109k', 'volume': '41', 'author': 'FG Njoroge', 'year': '2008', 'unstructured': 'Njoroge, F. G. et al. Challenges in modern drug discovery: a case study ' 'of boceprevir, an HCV protease inhibitor for the treatment of hepatitis ' 'C virus infection. Acc. Chem. Res. 41, 50–59 (2008).', 'journal-title': 'Acc. Chem. Res.'}, { 'key': '42102_CR8', 'doi-asserted-by': 'publisher', 'first-page': '1313', 'DOI': '10.1016/j.str.2020.10.007', 'volume': '28', 'author': 'DW Kneller', 'year': '2020', 'unstructured': 'Kneller, D. W. et al. Malleability of the SARS-CoV-2 3CL Mpro ' 'active-site cavity facilitates binding of clinical antivirals. Structure ' '28, 1313–1320 (2020).', 'journal-title': 'Structure'}, { 'key': '42102_CR9', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41467-020-18233-x', 'volume': '11', 'author': 'L Fu', 'year': '2020', 'unstructured': 'Fu, L. et al. Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 ' 'by targeting its main protease. Nat. Commun. 11, 4417 (2020).', 'journal-title': 'Nat. Commun.'}, { 'key': '42102_CR10', 'doi-asserted-by': 'publisher', 'first-page': '12725', 'DOI': '10.1021/acs.jmedchem.0c01063', 'volume': '63', 'author': 'RL Hoffman', 'year': '2020', 'unstructured': 'Hoffman, R. L. et al. Discovery of ketone-based covalent inhibitors of ' 'coronavirus 3CL proteases for the potential therapeutic treatment of ' 'COVID-19. J. Med. Chem. 63, 12725–12747 (2020).', 'journal-title': 'J. Med. Chem.'}, { 'key': '42102_CR11', 'doi-asserted-by': 'publisher', 'first-page': '4085', 'DOI': '10.1111/febs.12936', 'volume': '281', 'author': 'R Hilgenfeld', 'year': '2014', 'unstructured': 'Hilgenfeld, R. From SARS to MERS: crystallographic studies on ' 'coronaviral proteases enable antiviral drug design. FEBS J. 281, ' '4085–4096 (2014).', 'journal-title': 'FEBS J.'}, { 'key': '42102_CR12', 'doi-asserted-by': 'publisher', 'first-page': '6595', 'DOI': '10.1021/acs.jmedchem.5b01461', 'volume': '59', 'author': 'T Pillaiyar', 'year': '2016', 'unstructured': 'Pillaiyar, T. et al. An overview of severe acute respiratory ' 'syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics ' 'and small molecule chemotherapy. J. Med. Chem. 59, 6595–6628 (2016).', 'journal-title': 'J. Med. Chem.'}, { 'key': '42102_CR13', 'doi-asserted-by': 'publisher', 'first-page': '2716', 'DOI': '10.1021/acs.jmedchem.0c01140', 'volume': '65', 'author': 'R Cannalire', 'year': '2022', 'unstructured': 'Cannalire, R. et al. Targeting SARS-CoV-2 proteases and polymerase for ' 'COVID-19 treatment: state of the art and future opportunities. J. Med. ' 'Chem. 65, 2716–2746 (2022).', 'journal-title': 'J. Med. Chem.'}, { 'key': '42102_CR14', 'doi-asserted-by': 'publisher', 'first-page': 'e01819', 'DOI': '10.1128/JVI.01819-20', 'volume': '95', 'author': 'M de Vries', 'year': '2021', 'unstructured': 'de Vries, M. et al. A comparative analysis of SARS-CoV-2 antivirals ' 'characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment ' 'for COVID-19. J. Virol. 95, e01819 (2021).', 'journal-title': 'J. Virol.'}, { 'key': '42102_CR15', 'doi-asserted-by': 'publisher', 'first-page': '86', 'DOI': '10.1016/j.drudis.2014.09.014', 'volume': '20', 'author': 'A Tarcsay', 'year': '2015', 'unstructured': 'Tarcsay, A. & Keseru, G. M. Is there a link between selectivity and ' 'binding thermodynamics profiles? Drug Discov. Today 20, 86–94 (2015).', 'journal-title': 'Drug Discov. Today'}, { 'key': '42102_CR16', 'doi-asserted-by': 'publisher', 'first-page': '1', 'DOI': '10.1016/j.ab.2016.08.023', 'volume': '513', 'author': 'A Schon', 'year': '2016', 'unstructured': 'Schon, A. & Freire, E. Enthalpy screen of drug candidates. Anal. ' 'Biochem. 513, 1–6 (2016).', 'journal-title': 'Anal. Biochem.'}, { 'key': '42102_CR17', 'doi-asserted-by': 'publisher', 'first-page': '869', 'DOI': '10.1016/j.drudis.2008.07.005', 'volume': '13', 'author': 'E Freire', 'year': '2008', 'unstructured': 'Freire, E. Do enthalpy and entropy distinguish first in class from best ' 'in class? Drug Discov. Today 13, 869–874 (2008).', 'journal-title': 'Drug Discov. Today'}, { 'key': '42102_CR18', 'doi-asserted-by': 'publisher', 'first-page': '289', 'DOI': '10.1038/s41586-020-2223-y', 'volume': '582', 'author': 'Z Jin', 'year': '2020', 'unstructured': 'Jin, Z. et al. Structure of Mpro from SARS-CoV-2 and discovery of its ' 'inhibitors. Nature 582, 289–293 (2020).', 'journal-title': 'Nature'}, { 'key': '42102_CR19', 'doi-asserted-by': 'publisher', 'first-page': '909', 'DOI': '10.1038/nrd3845', 'volume': '11', 'author': 'J Bowes', 'year': '2012', 'unstructured': 'Bowes, J. et al. Reducing safety-related drug attrition: the use of in ' 'vitro pharmacological profiling. Nat. Rev. Drug Discov. 11, 909–922 ' '(2012).', 'journal-title': 'Nat. Rev. Drug Discov.'}, { 'key': '42102_CR20', 'doi-asserted-by': 'publisher', 'first-page': '1374', 'DOI': '10.1126/science.abf1611', 'volume': '371', 'author': 'J Qiao', 'year': '2021', 'unstructured': 'Qiao, J. et al. SARS-CoV-2 M(pro) inhibitors with antiviral activity in ' 'a transgenic mouse model. Science 371, 1374–1378 (2021).', 'journal-title': 'Science'}, { 'key': '42102_CR21', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41467-022-29915-z', 'volume': '13', 'author': 'DW Kneller', 'year': '2022', 'unstructured': 'Kneller, D. W. et al. Covalent narlaprevir- and boceprevir-derived ' 'hybrid inhibitors of SARS-CoV-2 main protease. Nat. Commun. 13, 2268 ' '(2022).', 'journal-title': 'Nat. Commun.'}, { 'key': '42102_CR22', 'doi-asserted-by': 'publisher', 'first-page': '2292', 'DOI': '10.1021/acscatal.8b05051', 'volume': '9', 'author': 'YH Wang', 'year': '2019', 'unstructured': 'Wang, Y. H. et al. Covalent inhibition mechanism of antidiabetic ' 'drugs-vildagliptin vs saxagliptin. Acs Catal. 9, 2292–2302 (2019).', 'journal-title': 'Acs Catal.'}, { 'key': '42102_CR23', 'doi-asserted-by': 'publisher', 'first-page': '881', 'DOI': '10.1038/s41573-022-00542-z', 'volume': '21', 'author': 'L Boike', 'year': '2022', 'unstructured': 'Boike, L., Henning, N. J. & Nomura, D. K. Advances in covalent drug ' 'discovery. Nat. Rev. Drug Discov. 21, 881–898 (2022).', 'journal-title': 'Nat. Rev. Drug Discov.'}, { 'key': '42102_CR24', 'doi-asserted-by': 'publisher', 'first-page': '67', 'DOI': '10.1016/j.jbbm.2005.12.008', 'volume': '67', 'author': 'F van den Ent', 'year': '2006', 'unstructured': 'van den Ent, F. & Lowe, J. RF cloning: a restriction-free method for ' 'inserting target genes into plasmids. J. Biochem. Biophys. Methods 67, ' '67–74 (2006).', 'journal-title': 'J. Biochem. Biophys. Methods'}, { 'key': '42102_CR25', 'doi-asserted-by': 'publisher', 'first-page': '170', 'DOI': '10.1007/s41365-019-0683-2', 'volume': '30', 'author': 'W Zhang', 'year': '2019', 'unstructured': 'Zhang, W. et al. The protein complex crystallography beamline (BL19U1) ' 'at the shanghai synchrotron radiation facility. Nucl. Sci. Tech. 30, 170 ' '(2019).', 'journal-title': 'Nucl. Sci. Tech.'}, { 'key': '42102_CR26', 'doi-asserted-by': 'publisher', 'first-page': '472', 'DOI': '10.1107/S1600576719001183', 'volume': '52', 'author': 'F Yu', 'year': '2019', 'unstructured': 'Yu, F. et al. Aquarium: an automatic data-processing and experiment ' 'information management system for biological macromolecular ' 'crystallography beamlines. J. Appl. Crystallogr. 52, 472–477 (2019).', 'journal-title': 'J. Appl. Crystallogr.'}, { 'key': '42102_CR27', 'doi-asserted-by': 'publisher', 'first-page': '859', 'DOI': '10.1107/S0907444906019949', 'volume': '62', 'author': 'W Minor', 'year': '2006', 'unstructured': 'Minor, W. et al. HKL-3000: the integration of data reduction and ' 'structure solution-from diffraction images to an initial model in ' 'minutes. Acta Crystallogr. D 62, 859–866 (2006).', 'journal-title': 'Acta Crystallogr. D'}, { 'key': '42102_CR28', 'doi-asserted-by': 'publisher', 'first-page': '760', 'DOI': '10.1107/S0907444994003112', 'volume': '50', 'author': 'Collaborative C. P.', 'year': '1994', 'unstructured': 'Collaborative C. P. The CCP4 suite: programs for protein ' 'crystallography. Acta Crystallogr. D 50, 760–763 (1994).', 'journal-title': 'Acta Crystallogr. D'}, { 'key': '42102_CR29', 'doi-asserted-by': 'publisher', 'first-page': '1167', 'DOI': '10.1038/s41401-020-0483-6', 'volume': '41', 'author': 'H Su', 'year': '2020', 'unstructured': 'Su, H. et al. Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian ' 'preparations and bioactive ingredients. Acta Pharmacol. Sin. 41, ' '1167–1177 (2020).', 'journal-title': 'Acta Pharmacol. Sin.'}, { 'key': '42102_CR30', 'doi-asserted-by': 'publisher', 'first-page': '2126', 'DOI': '10.1107/S0907444904019158', 'volume': '60', 'author': 'P Emsley', 'year': '2004', 'unstructured': 'Emsley, P. & Cowtan, K. Coot: model-building tools for molecular ' 'graphics. Acta Crystallogr. D 60, 2126–2132 (2004).', 'journal-title': 'Acta Crystallogr. D'}, { 'key': '42102_CR31', 'doi-asserted-by': 'publisher', 'first-page': '1948', 'DOI': '10.1107/S0907444902016657', 'volume': '58', 'author': 'PD Adams', 'year': '2002', 'unstructured': 'Adams, P. D. et al. PHENIX: building new software for automated ' 'crystallographic structure determination. Acta Crystallogr. D 58, ' '1948–1954 (2002).', 'journal-title': 'Acta Crystallogr. D'}], 'container-title': 'Nature Communications', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://www.nature.com/articles/s41467-023-42102-y.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41467-023-42102-y', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41467-023-42102-y.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 11, 17]], 'date-time': '2023-11-17T06:15:50Z', 'timestamp': 1700201750000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.nature.com/articles/s41467-023-42102-y'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2023, 10, 13]]}, 'references-count': 31, 'journal-issue': {'issue': '1', 'published-online': {'date-parts': [[2023, 12]]}}, 'alternative-id': ['42102'], 'URL': 'http://dx.doi.org/10.1038/s41467-023-42102-y', 'relation': {}, 'ISSN': ['2041-1723'], 'subject': [ 'General Physics and Astronomy', 'General Biochemistry, Genetics and Molecular Biology', 'General Chemistry', 'Multidisciplinary'], 'container-title-short': 'Nat Commun', 'published': {'date-parts': [[2023, 10, 13]]}, 'assertion': [ { 'value': '18 April 2023', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '25 September 2023', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '13 October 2023', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': 'X.J., Y.X., L.Z., H.S., Q.Z., W.Z., W.S., J.S., G.X., and H.J. are co-inventors ' 'of the patent (CN202111168232.4, China) that cover 3CL^pro inhibitors ' 'included in this study. F. Z., L.J., X.H., P.C., S.P., and R.T. are employers ' 'of Simcere Co. Ltd. F. Z., L.J., X.H., P.C., S.P., and R.T. are shareholders in ' 'Simcere Co. Ltd. All other authors declare no competing interests.', 'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '6463'}