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Binding Adaptation of GS-441524 Diversifies Macro Domains and Downregulates SARS-CoV-2 de-MARylation Capacity.
Tsika, Aikaterini C; Gallo, Angelo; Fourkiotis, Nikolaos K; Argyriou, Aikaterini I; Sreeramulu, Sridhar; Löhr, Frank; Rogov, Vladimir V; Richter, Christian; Linhard, Verena; Gande, Santosh L; Altincekic, Nadide; Krishnathas, Robin; Elamri, Isam; Schwalbe, Harald; Wollenhaupt, Jan; Weiss, Manfred S; Spyroulias, Georgios A.
  • Tsika AC; Department of Pharmacy, University of Patras, GR-26504 Patras, Greece. Electronic address: https://twitter.com/@katerina_tsika.
  • Gallo A; Department of Pharmacy, University of Patras, GR-26504 Patras, Greece. Electronic address: https://twitter.com/@AngeloGallo83.
  • Fourkiotis NK; Department of Pharmacy, University of Patras, GR-26504 Patras, Greece.
  • Argyriou AI; Department of Pharmacy, University of Patras, GR-26504 Patras, Greece.
  • Sreeramulu S; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany.
  • Löhr F; Institute for Biophysical Chemistry, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • Rogov VV; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany; Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • Richter C; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany.
  • Linhard V; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany.
  • Gande SL; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany.
  • Altincekic N; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany.
  • Krishnathas R; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany.
  • Elamri I; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany.
  • Schwalbe H; Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany. Electronic address: schwalbe@nmr.uni-frankfurt.de.
  • Wollenhaupt J; Macromolecular Crystallography, Helmholtz-Zentrum Berlin, Albert-Einstein-Straße 15, D-12489 Berlin, Germany. Electronic address: https://twitter.com/@Jan_Wollenhaupt.
  • Weiss MS; Macromolecular Crystallography, Helmholtz-Zentrum Berlin, Albert-Einstein-Straße 15, D-12489 Berlin, Germany. Electronic address: https://twitter.com/@ManfredSWeiss.
  • Spyroulias GA; Department of Pharmacy, University of Patras, GR-26504 Patras, Greece. Electronic address: G.A.Spyroulias@upatras.gr.
J Mol Biol ; 434(16): 167720, 2022 08 30.
Article in English | MEDLINE | ID: covidwho-2028233
ABSTRACT
Viral infection in cells triggers a cascade of molecular defense mechanisms to maintain host-cell homoeostasis. One of these mechanisms is ADP-ribosylation, a fundamental post-translational modification (PTM) characterized by the addition of ADP-ribose (ADPr) on substrates. Poly(ADP-ribose) polymerases (PARPs) are implicated in this process and they perform ADP-ribosylation on host and pathogen proteins. Some viral families contain structural motifs that can reverse this PTM. These motifs known as macro domains (MDs) are evolutionarily conserved protein domains found in all kingdoms of life. They are divided in different classes with the viral belonging to Macro-D-type class because of their properties to recognize and revert the ADP-ribosylation. Viral MDs are potential pharmaceutical targets, capable to counteract host immune response. Sequence and structural homology between viral and human MDs are an impediment for the development of new active compounds against their function. Remdesivir, is a drug administrated in viral infections inhibiting viral replication through RNA-dependent RNA polymerase (RdRp). Herein, GS-441524, the active metabolite of the remdesivir, is tested as a hydrolase inhibitor for several viral MDs and for its binding to human homologs found in PARPs. This study presents biochemical and biophysical studies, which indicate that GS-441524 selectively modifies SARS-CoV-2 MD de-MARylation activity, while it does not interact with hPARP14 MD2 and hPARP15 MD2. The structural investigation of MD•GS-441524 complexes, using solution NMR and X-ray crystallography, discloses the impact of certain amino acids in ADPr binding cavity suggesting that F360 and its adjacent residues tune the selective binding of the inhibitor to SARS-CoV-2 MD.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Adenosine / Poly(ADP-ribose) Polymerases / ADP-Ribosylation / Coronavirus Protease Inhibitors / SARS-CoV-2 Limits: Humans Language: English Journal: J Mol Biol Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Adenosine / Poly(ADP-ribose) Polymerases / ADP-Ribosylation / Coronavirus Protease Inhibitors / SARS-CoV-2 Limits: Humans Language: English Journal: J Mol Biol Year: 2022 Document Type: Article