Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors
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 ofmore »
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1766903
- Alternate Identifier(s):
- OSTI ID: 1813416
- Grant/Contract Number:
- AC02-76SF00515; AC02-06CH11357; SC0012704; KP1605010; P30 GM124165; P30 GM133893; AC02-05CH11231
- Resource Type:
- Published Article
- Journal Name:
- Progress in Biophysics and Molecular Biology
- Additional Journal Information:
- Journal Name: Progress in Biophysics and Molecular Biology Journal Volume: 163 Journal Issue: C; Journal ID: ISSN 0079-6107
- Publisher:
- Elsevier
- Country of Publication:
- United Kingdom
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; SARS-CoV-2 Nsp3 macrodomain; Poly(ADP-Ribose) glycohydrolase (PARG); PARG inhibitor (PARGi); Evolutionary trace (ET); In silico screening; Drug discovery
Citation Formats
Brosey, Chris A., Houl, Jerry H., Katsonis, Panagiotis, Balapiti-Modarage, Lakshitha P. F., Bommagani, Shobanbabu, Arvai, Andy, Moiani, Davide, Bacolla, Albino, Link, Todd, Warden, Leslie S., Lichtarge, Olivier, Jones, Darin E., Ahmed, Zamal, and Tainer, John A. Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors. United Kingdom: N. p., 2021.
Web. doi:10.1016/j.pbiomolbio.2021.02.002.
Brosey, Chris A., Houl, Jerry H., Katsonis, Panagiotis, Balapiti-Modarage, Lakshitha P. F., Bommagani, Shobanbabu, Arvai, Andy, Moiani, Davide, Bacolla, Albino, Link, Todd, Warden, Leslie S., Lichtarge, Olivier, Jones, Darin E., Ahmed, Zamal, & Tainer, John A. Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors. United Kingdom. https://doi.org/10.1016/j.pbiomolbio.2021.02.002
Brosey, Chris A., Houl, Jerry H., Katsonis, Panagiotis, Balapiti-Modarage, Lakshitha P. F., Bommagani, Shobanbabu, Arvai, Andy, Moiani, Davide, Bacolla, Albino, Link, Todd, Warden, Leslie S., Lichtarge, Olivier, Jones, Darin E., Ahmed, Zamal, and Tainer, John A. Sun .
"Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors". United Kingdom. https://doi.org/10.1016/j.pbiomolbio.2021.02.002.
@article{osti_1766903,
title = {Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors},
author = {Brosey, Chris A. and Houl, Jerry H. and Katsonis, Panagiotis and Balapiti-Modarage, Lakshitha P. F. and Bommagani, Shobanbabu and Arvai, Andy and Moiani, Davide and Bacolla, Albino and Link, Todd and Warden, Leslie S. and Lichtarge, Olivier and Jones, Darin E. and Ahmed, Zamal and Tainer, John A.},
abstractNote = {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.},
doi = {10.1016/j.pbiomolbio.2021.02.002},
journal = {Progress in Biophysics and Molecular Biology},
number = C,
volume = 163,
place = {United Kingdom},
year = {Sun Aug 01 00:00:00 EDT 2021},
month = {Sun Aug 01 00:00:00 EDT 2021}
}
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