Structural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr

• 成果类型: Article
• 署名作者: Kabinger, Florian; Doze, Valerie; Schmitzova, Jana; Lidschreiber, Michael; Dienemann, Christian; Cramer, Patrick
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9670
• DOI: 10.1073/pnas.2419854122
• 发表日期: 2025-03-11
• 关键词: dependent rna-polymerase; cation-pi interactions; cryo-em; complexes; stacking; binding

摘要

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 IC50 of 5 mu M 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.