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U.S.A."],"published-print":{"date-parts":[[2025,3,11]]},"abstract":"<jats:p>\n                    Targeting the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 with small molecules is a promising therapeutic strategy against COVID-19, but potent and safe inhibitors are lacking. HeE1-2Tyr, a nonnucleoside inhibitor of Dengue virus RdRp, was also shown to inhibit SARS-CoV-2 RdRp in vitro and to have antiviral activity in cells, but the underlying mechanism remains unclear. Here, we elucidate the molecular mechanism of HeE1-2Tyr-mediated SARS-CoV-2 RdRp inhibition. Biochemical assays confirm that HeE1-2Tyr inhibits RdRp with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 5 \u00b5M and show that it competes with RNA binding to RdRp in vitro. Structural analysis using cryo-EM reveals that a stack of three HeE1-2Tyr molecules binds to the RNA binding site of RdRp. The identification of the conserved HeE1-2Tyr binding site and its intriguing inhibition mechanism of three stacked molecules that outcompete RNA may facilitate further development of pan-corona nonnucleoside inhibitors.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2419854122","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T10:51:56Z","timestamp":1741085516000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":10,"title":["Structural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr"],"prefix":"10.1073","volume":"122","author":[{"given":"Florian","family":"Kabinger","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Doze","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Schmitzov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lidschreiber","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Dienemann","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5454-7755","authenticated-orcid":false,"given":"Patrick","family":"Cramer","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"World Health Organization. 2023 data.who.int WHO Coronavirus (COVID-19) dashboard > Deaths. 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