Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors

Chris A Brosey, Jerry H. Houl, Panagiotis Katsonis, Lakshitha P.F. Balapiti-Modarage, Shobanbabu Bommagani, Andy Arvai, Davide Moiani, Albino Bacolla, Todd M Link, Leslie S. Warden, Olivier Lichtarge, Darin E. Jones, Zamal Ahmed, John A. Tainer

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Arrival of the novel SARS-CoV-2 has launched a worldwide effort to identify both pre-approved and novel therapeutics targeting the viral proteome, highlighting the urgent need for efficient drug discovery strategies. Even with effective vaccines, infection is possible, and at-risk populations would benefit from effective drug compounds that reduce the lethality and lasting damage of COVID-19 infection. The CoV-2 MacroD-like macrodomain (Mac1) is implicated in viral pathogenicity by disrupting host innate immunity through its mono (ADP-ribosyl) hydrolase activity, making it a prime target for antiviral therapy. We therefore solved the structure of CoV-2 Mac1 from non-structural protein 3 (Nsp3) and applied structural and sequence-based genetic tracing, including newly determined A. pompejana MacroD2 and GDAP2 amino acid sequences, to compare and contrast CoV-2 Mac1 with the functionally related human DNA-damage signaling factor poly (ADP-ribose) glycohydrolase (PARG). Previously, identified targetable features of the PARG active site allowed us to develop a pharmacologically useful PARG inhibitor (PARGi). Here, we developed a focused chemical library and determined 6 novel PARGi X-ray crystal structures for comparative analysis. We applied this knowledge to discovery of CoV-2 Mac1 inhibitors by combining computation and structural analysis to identify PARGi fragments with potential to bind the distal-ribose and adenosyl pockets of the CoV-2 Mac1 active site. Scaffold development of these PARGi fragments has yielded two novel compounds, PARG-345 and PARG-329, that crystallize within the Mac1 active site, providing critical structure-activity data and a pathway for inhibitor optimization. The reported structural findings demonstrate ways to harness our PARGi synthesis and characterization pipeline to develop CoV-2 Mac1 inhibitors targeting the ADP-ribose active site. Together, these structural and computational analyses reveal a path for accelerating development of antiviral therapeutics from pre-existing drug optimization pipelines.

Original languageEnglish (US)
Pages (from-to)171-186
Number of pages16
JournalProgress in Biophysics and Molecular Biology
Volume163
DOIs
StatePublished - Aug 2021

Keywords

  • Drug discovery
  • Evolutionary trace (ET)
  • In silico screening
  • PARG inhibitor (PARGi)
  • Poly(ADP-Ribose) glycohydrolase (PARG)
  • SARS-CoV-2 Nsp3 macrodomain

ASJC Scopus subject areas

  • Biophysics
  • Molecular Biology

Fingerprint

Dive into the research topics of 'Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors'. Together they form a unique fingerprint.

Cite this