{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:28:15Z","timestamp":1785407295790,"version":"3.56.0"},"reference-count":29,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2025,12,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M\n                      <jats:sup>pro<\/jats:sup>\n                      ) is a clinically validated target for the treatment of coronavirus disease 2019 (COVID-19). Here, we report the hit-to-lead discovery of a new nitrile-based inhibitor,\n                      <jats:bold>H135<\/jats:bold>\n                      , of SARS-CoV-2 M\n                      <jats:sup>pro<\/jats:sup>\n                      from a series of chemical modifications of a nitrile-warhead-containing compound guided by its 1.8 \u00c5 high-resolution crystal structure in complex with SARS-CoV-2 M\n                      <jats:sup>pro<\/jats:sup>\n                      .\n                      <jats:bold>H135<\/jats:bold>\n                      exhibited potent and selective inhibition of SARS-CoV-2 M\n                      <jats:sup>pro<\/jats:sup>\n                      with IC\n                      <jats:sub>50<\/jats:sub>\n                      of 12.7 nM and exerted broad anti-SARS-CoV-2 activity in VeroE6-TMPRSS2 cells. Furthermore,\n                      <jats:bold>H135<\/jats:bold>\n                      -treated golden Syrian hamsters demonstrated significantly lower respiratory tract viral burden compared with solvent-treated control hamsters.\n                      <jats:bold>H135<\/jats:bold>\n                      may serve as a new lead for developing antiviral therapeutics for SARS-CoV-2 infection.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        In this study, a structure-guided hit-to-lead strategy was employed to develop a nanomolar potent small molecule inhibitor H135 of SARS-CoV-2 M\n                        <jats:sup>pro<\/jats:sup>\n                        with strong anti-SARS-CoV-2 infection activity in cell cultures and animals. H135 may serve as a new lead for developing antiviral agents targeting the virus\u2019s main protease M\n                        <jats:sup>pro<\/jats:sup>\n                        .\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01001-25","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T15:34:24Z","timestamp":1763134464000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Structure-guided discovery of a small molecule inhibitor of SARS-CoV-2 main protease with potent\n                    <i>in vitro<\/i>\n                    and\n                    <i>in vivo<\/i>\n                    antiviral activities"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7996-1119","authenticated-orcid":false,"given":"Shuofeng","family":"Yuan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02zhqgq86","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong","place":["Pokfulam, China"]},{"name":"InnoHK (Centre for Virology, Vaccinology and Therapeutics), Hong Kong Science and Technology Park","place":["Hong Kong Special Administrative Region, China"]},{"id":[{"id":"https:\/\/ror.org\/02zhqgq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Diseases and Microbiology, The University of Hong Kong-Shenzhen Hospital","place":["Shenzhen, 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