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An Update on the Current State of SARS-CoV-2 Mac1 Inhibitors

PATHOGENS (2023)

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Article Multidisciplinary Sciences

Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2

Stefan Gahbauera et al.

Summary: This study reports the discovery and development of chemical scaffolds that bind to the nonstructural protein 3 (NSP3) of SARS-CoV-2. Through computational design and structural characterization, several potent ligands were identified, providing potential therapeutic options for COVID-19.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2023)

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Article Microbiology

Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors

Marion Schuller et al.

Summary: The COVID-19 pandemic has demonstrated the importance of preparedness for viral disease outbreaks. The NSP3 macrodomain of coronaviruses has been identified as a potential target for antiviral agents. By screening efforts, several small molecules and FDA-approved drugs have been discovered as inhibitors of the NSP3 macrodomain, providing valuable information for inhibitor development.

PATHOGENS (2023)

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Article Multidisciplinary Sciences

SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice

Yousef M. Alhammad et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2023)

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Article Biochemistry & Molecular Biology

Drug similarity and structure-based screening of medicinal compounds to target macrodomain-I from SARS-CoV-2 to rescue the host immune system: a molecular dynamics study

Zainib Babar et al.

Summary: The outbreak of the recent coronavirus poses significant risks to public health, and researchers have identified potential drug candidates that can inhibit SARs-CoV-2 by targeting key residues. Experimental testing is recommended to confirm their antiviral effects.

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS (2022)

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Article Biochemistry & Molecular Biology

High-Throughput Activity Assay for Screening Inhibitors of the SARS-CoV-2 Mac1 Macrodomain

Morgan Dasovich et al.

Summary: Viral macrodomains are crucial for virus replication and pathogenesis, making them a promising target for antiviral therapy. Dasatinib has been identified as a potential ADP-ribosylhydrolase inhibitor, showing effectiveness against SARS-CoV-2 and MERS-CoV, but not affecting the closest human homologue MacroD2. This study demonstrates the feasibility of identifying selective inhibitors based on ADP-ribosylhydrolase activity and provides a potential avenue for developing better macrodomain inhibitors as antiviral therapies for SARS-CoV-2 and other viral threats.

ACS CHEMICAL BIOLOGY (2022)

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Article Multidisciplinary Sciences

The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and x-ray diffraction at room temperature

Galen J. Correy et al.

Summary: This study determined the crystal structures of the nonstructural protein 3 (NSP3) macrodomain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), revealing the reorganization of water networks upon binding of ADP-ribose and other ligands. The catalytic mechanism of coronavirus macrodomains was found to be distinct from that of human macrodomains, providing insights for the development of inhibitors.

SCIENCE ADVANCES (2022)

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Article Pharmacology & Pharmacy

Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening

Anu Roy et al.

Summary: This study focuses on screening for potential inhibitors of the SARS-CoV-2 conserved macrodomain (Mac1). Five compounds from three chemotypes were identified, which show inhibitory effects on Mac1-ADP-ribose binding, ADP-ribosylhydrolase activity, and direct Mac1 binding, making them strong candidates for the development of highly effective Mac1 inhibitors.

ANTIVIRAL RESEARCH (2022)

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Article Biochemistry & Molecular Biology

Design, synthesis and evaluation of inhibitors of the SARS-CoV-2 nsp3 macrodomain

Lavinia M. Sherrill et al.

Summary: A series of amino acid based compounds were designed and synthesized to investigate their inhibitory activity against the SARS-CoV-2 nsp3 macrodomain. Compound 15c was identified as a low-micromolar inhibitor and demonstrated selectivity for coronavirus macrodomains.

BIOORGANIC & MEDICINAL CHEMISTRY (2022)

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Article Biochemistry & Molecular Biology

Binding Adaptation of GS-441524 Diversifies Macro Domains and Down- regulates SARS-CoV-2 de-MARylation Capacity

Aikaterini C. Tsika et al.

Summary: Viral infection triggers molecular defense mechanisms, including ADP-ribosylation. Viral macro domains, which can reverse ADP-ribosylation, are potential pharmaceutical targets. GS-441524, a metabolite of remdesivir, selectively inhibits viral macro domains.

JOURNAL OF MOLECULAR BIOLOGY (2022)

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Article Biology

Identification of FDA approved drugs and nucleoside analogues as potential SARS-CoV-2 A1pp domain inhibitor: An in silico study

Atul Kumar Singh et al.

Summary: In this study, potential therapeutic molecule NA1 was identified as a lead inhibitor for SARS-CoV-2 A1pp domain through in silico screening. The compound demonstrated strong binding affinity and stable complex formation, with promising potential for future testing and development as therapeutics against human coronavirus. The molecular dynamics simulation and binding free energy analysis further validated the efficacy of NA1, highlighting its potential as a promising candidate for anti-SARS-CoV-2 drug development.

COMPUTERS IN BIOLOGY AND MEDICINE (2021)

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Review Biochemistry & Molecular Biology

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

Chris A. Brosey et al.

Summary: The study investigated the structure of CoV-2 Mac1 and its relationship with the human DNA-damage signaling factor PARG, leading to the discovery of two novel compounds, PARG-345 and PARG-329, which crystallize within the Mac1 active site, providing critical structure-activity data.

PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY (2021)

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Article Chemistry, Medicinal

Structural Insights into Plasticity and Discovery of Remdesivir Metabolite GS-441524 Binding in SARS-CoV-2 Macrodomain

Xiaomin Ni et al.

Summary: The nsP3 macrodomain is crucial in regulating the host immune response during SARS-CoV-2 infection by recognizing and removing posttranslational ADP-ribosylation sites. Targeting this protein domain could provide a therapeutic strategy for combating virus pandemics. Crystal structures complexed with diverse nucleotides, small molecules, and nucleotide analogues, including active metabolites of remdesivir, provide valuable insights for inhibitor development.

ACS MEDICINAL CHEMISTRY LETTERS (2021)

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Article Multidisciplinary Sciences

Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking

Marion Schuller et al.

Summary: A large-scale crystallographic screening and computational docking effort identified new chemical matter targeting the active site of the SARS-CoV-2 macrodomain, providing a starting point for the development of potent macro-domain inhibitors.

SCIENCE ADVANCES (2021)

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Article Biochemical Research Methods

High-Throughput Screening and Quantum Mechanics for Identifying Potent Inhibitors Against Mac1 Domain of SARS-CoV-2 Nsp3

Chandrabose Selvaraj et al.

Summary: The Mac1 enzyme encoded by SARS-CoV-2 is considered an ideal drug target with broad antiviral activity against coronaviruses. Studies show highly conserved residues in the binding pocket for Mac1, which is closely related to its interaction with ADP-ribose.

IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS (2021)

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Article Multidisciplinary Sciences

Exploring protein hotspots by optimized fragment pharmacophores

David Bajusz et al.

Summary: Fragment-based drug design offers a bottom-up approach for drug development, combining pharmacophores and protein hotspots theory to create a design protocol for fragment libraries named SpotXplorer, demonstrating effectiveness on both established and emerging drug targets.

NATURE COMMUNICATIONS (2021)

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Article Biochemical Research Methods

A molecular toolbox for ADP-ribosyl binding proteins

Sven T. Sowa et al.

Summary: A robust and accessible assay for proteins interacting with ADP-ribosyl groups is presented, utilizing a C-terminal tag based on a Gi protein alpha subunit peptide for site-specific introduction of mono- and poly-ADP-ribosyl groups or analogs. This technology generates strong FRET partners by fusing the GAP-tag and ADP-ribosyl binders with fluorescent proteins, and is applicable for high-throughput screening.

CELL REPORTS METHODS (2021)

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Article Biochemical Research Methods

Discovery of Drug-Like Ligands for the Mac1 Domain of SARS-CoV-2 Nsp3

Rajdeep S. Virdi et al.

SLAS DISCOVERY (2020)

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Article Biochemistry & Molecular Biology

Viral macrodomains: a structural and evolutionary assessment of the pharmacological potential

Johannes Gregor Matthias Rack et al.

OPEN BIOLOGY (2020)

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Article Microbiology

The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression

Matthew E. Grunewald et al.

PLOS PATHOGENS (2019)

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Article Microbiology

Macrodomain ADP-ribosylhydrolase and the pathogenesis of infectious diseases

Anthony K. L. Leung et al.

PLOS PATHOGENS (2018)

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Article Biochemical Research Methods

Identification of Poly(ADP-Ribose) Polymerase Macrodomain Inhibitors Using an AlphaScreen Protocol

Torun Ekblad et al.

SLAS DISCOVERY (2018)

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Article Multidisciplinary Sciences

ADP-ribosyl-binding and hydrolase activities of the alphavirus nsP3 macrodomain are critical for initiation of virus replication

Rachy Abraham et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2018)

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Article Multidisciplinary Sciences

ADP-ribosylhydrolase activity of Chikungunya virus macrodomain is critical for virus replication and virulence

Robert Lyle McPherson et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2017)

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Article Multidisciplinary Sciences

The conserved macrodomains of the non-structural proteins of Chikungunya virus and other pathogenic positive strand RNA viruses function as mono-ADP-ribosylhydrolases

Laura Eckei et al.

SCIENTIFIC REPORTS (2017)

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Review Biochemistry & Molecular Biology

Macrodomains: Structure, Function, Evolution, and Catalytic Activities

Johannes Gregor Matthias Rack et al.

ANNUAL REVIEW OF BIOCHEMISTRY, VOL 85 (2016)

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Article Microbiology

The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection

Anthony R. Fehr et al.

MBIO (2016)

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Article Genetics & Heredity

The hepatitis E virus ORF1 'X-domain' residues form a putative macrodomain protein/Appr-1-pase catalytic-site, critical for viral RNA replication

Mohammad Khalid Parvez

GENE (2015)

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Article Virology

The nsp3 Macrodomain Promotes Virulence in Mice with Coronavirus-Induced Encephalitis

Anthony R. Fehr et al.

JOURNAL OF VIROLOGY (2015)

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Article Biochemistry & Molecular Biology

A family of macrodomain proteins reverses cellular mono-ADP-ribosylation

Gytis Jankevicius et al.

NATURE STRUCTURAL & MOLECULAR BIOLOGY (2013)

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Article Biochemistry & Molecular Biology

The macro domain is an ADP-ribose binding module

GI Karras et al.

EMBO JOURNAL (2005)

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Article Biochemistry & Molecular Biology

The crystal structure of AF1521 a protein from Archaeoglobus fulgidus with homology to the non-histone domain of MacroH2A

MD Allen et al.

JOURNAL OF MOLECULAR BIOLOGY (2003)

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