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10.1016/j.pbiomolbio.2021.02.002

http://scihub22266oqcxt.onion/10.1016/j.pbiomolbio.2021.02.002
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33636189!7901392!33636189
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suck abstract from ncbi


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pmid33636189      Prog+Biophys+Mol+Biol 2021 ; 163 (ä): 171-186
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  • Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors #MMPMID33636189
  • Brosey CA; Houl JH; Katsonis P; Balapiti-Modarage LPF; Bommagani S; Arvai A; Moiani D; Bacolla A; Link T; Warden LS; Lichtarge O; Jones DE; Ahmed Z; Tainer JA
  • Prog Biophys Mol Biol 2021[Aug]; 163 (ä): 171-186 PMID33636189show ga
  • 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.
  • |Amino Acid Sequence[MESH]
  • |Antiviral Agents/*chemistry/pharmacology[MESH]
  • |COVID-19 Drug Treatment[MESH]
  • |Catalytic Domain[MESH]
  • |Coronavirus Papain-Like Proteases/*metabolism[MESH]
  • |Crystallography, X-Ray[MESH]
  • |Drug Discovery[MESH]
  • |Enzyme Inhibitors/*chemistry/pharmacology[MESH]
  • |Glycoside Hydrolases/*antagonists & inhibitors[MESH]
  • |Humans[MESH]
  • |Models, Molecular[MESH]
  • |Protein Domains[MESH]
  • |SARS-CoV-2/drug effects/metabolism[MESH]
  • |Small Molecule Libraries/*chemistry/pharmacology[MESH]
  • |Structure-Activity Relationship[MESH]


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