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TitleStructural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 10, Page e2419854122, Year 2025
Publish dateMar 11, 2025
AuthorsFlorian Kabinger / Valerie Doze / Jana Schmitzová / Michael Lidschreiber / Christian Dienemann / Patrick Cramer /
PubMed AbstractTargeting 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 ...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 of 5 µM 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.
External linksProc Natl Acad Sci U S A / PubMed:40035759 / PubMed Central
MethodsEM (single particle)
Resolution2.98 Å
Structure data

52704

9i81

EMDB-52704, PDB-9i81:
SARS-CoV-2 RdRp bound to a stack of three HeE1-2Tyr molecules
Method: EM (single particle) / Resolution: 2.98 Å

Chemicals

ChemComp-6CJ:
N-[8-(cyclohexyloxy)-1-oxo-2-phenyl-1H-pyrido[2,1-b][1,3]benzothiazole-4-carbonyl]-L-tyrosine

Source
  • severe acute respiratory syndrome coronavirus 2
KeywordsVIRAL PROTEIN / SARS-CoV-2 RdRp Small molecule inhibitor

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