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

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

  • Prog Biophys Mol Biol. 2021 Aug;163:171-186. doi: 10.1016/j.pbiomolbio.2021.02.002.
Chris A Brosey 1 Jerry H Houl 2 Panagiotis Katsonis 3 Lakshitha P F Balapiti-Modarage 4 Shobanbabu Bommagani 4 Andy Arvai 5 Davide Moiani 2 Albino Bacolla 2 Todd Link 2 Leslie S Warden 2 Olivier Lichtarge 3 Darin E Jones 4 Zamal Ahmed 6 John A Tainer 7
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA. Electronic address: [email protected].
  • 2 Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA.
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 4 Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
  • 5 Integrative Structural & Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
  • 6 Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA. Electronic address: [email protected].
  • 7 Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA; Department of Cancer Biology, M.D. Anderson Cancer Center, Houston, TX, 77030, USA; Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA. Electronic address: [email protected].
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.

Keywords

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

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