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A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase

Ashleigh Shannon1, Véronique Fattorini1, Bhawna Sama1

  • 1Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix Marseille Université, UMR 7257, Polytech Case 925, 13009, Marseille, France.

Nature Communications
|February 3, 2022
PubMed

Insights

The antiviral AT-527, converted to AT-9010, inhibits SARS-CoV-2 by terminating RNA synthesis and blocking NiRAN activity. This dual mechanism offers a promising COVID-19 treatment strategy.

Area of Science:

  • Virology
  • Structural Biology
  • Drug Discovery

Background:

  • Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2) causes COVID-19.
  • Antiviral therapies targeting viral replication are crucial for managing COVID-19.
  • The guanosine analog AT-527 is a potential therapeutic agent that has advanced to phase III clinical trials.

Purpose of the Study:

  • To elucidate the structural basis of AT-527's antiviral activity against SARS-CoV-2.
  • To investigate the interaction of AT-527's active metabolite, AT-9010, with the viral RNA-dependent RNA polymerase (RdRp).
  • To understand the dual mechanism of action of AT-527.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to determine the structure of the SARS-CoV-2 nsp12-nsp7-nsp82-RNA complex.
  • The structure revealed the binding sites and interactions of AT-9010 within the nsp12 enzyme.
  • Biochemical assays were employed to assess the inhibition of nucleotidyltransferase activity.

Main Results:

  • A 2.98 Å cryo-EM structure showed AT-9010 bound at three sites on nsp12.
  • One AT-9010 molecule was incorporated into the RNA strand, causing chain termination due to its modified ribose.
  • A second AT-9010 molecule bound to the NiRAN domain, competitively inhibiting its nucleotidyltransferase activity.

Conclusions:

  • AT-527, via AT-9010, exhibits a dual mechanism of action against SARS-CoV-2.
  • The drug terminates viral RNA synthesis by inhibiting the RdRp active site.
  • AT-9010 also inhibits the NiRAN domain's nucleotidyltransferase activity, providing a potent antiviral strategy.

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