Identification of Small-Molecule Inhibitors of the XendoU Endoribonucleases Family

Autor: Irene Bozzoni, Rino Ragno, Ubaldo Gioia, Pietro Laneve, Antonello Mai, Elisa Caffarelli
Přispěvatelé: Department of Medicinal Chemistry and Technologies, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Biology and Biotechnology 'Charles Darwin', Institute of Molecular Biology and Pathology, CNR, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], This work was supported by the European Union SIROCCO project (LSHG-CT-2006–07900), the European Science Foundation NuRNASu project , the Associazione Italiana per la Ricerca sul Cancro, the Italian Progetti di Ricerca di Interesse Nazionale, the Centro di Eccellenza Biologia eMedicina Molecolare (Rome, Italy), and the Fondazione Roma(Italy). U.G. was supported by a fellowship from the Fondazione Italiana per la Ricerca sul Cancro., European Project: LSHG-CT-2006–07900, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), CNR Istituto di Biologia e Patologia Molecolari [Roma] (CNR | IBPM), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR)
Jazyk: angličtina
Rok vydání: 2011
Předmět:
rna processing
autodock
endoribonucleases
structure-based drug design
xendou family
MESH: Catalytic Domain
Pregnancy Proteins
Xenopus Proteins
medicine.disease_cause
01 natural sciences
Biochemistry
Xenopus laevis
chemistry.chemical_compound
Endoribonucleases
Catalytic Domain
Drug Discovery
MESH: Animals
Enzyme Inhibitors
General Pharmacology
Toxicology and Pharmaceutics
MESH: Xenopus Proteins
Coronavirus
chemistry.chemical_classification
0303 health sciences
MESH: Pregnancy Proteins
Full Paper
biology
Full Papers
Small molecule
3. Good health
Cell biology
MESH: Enzyme Inhibitors
Molecular Medicine
structure‐based drug design
MESH: Endoribonucleases
MESH: Enzyme Activation
Small Molecule Libraries
03 medical and health sciences
Biosynthesis
MESH: Computer Simulation
MESH: Small Molecule Libraries
MESH: Xenopus laevis
medicine
Animals
Humans
Computer Simulation
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
030304 developmental biology
Pharmacology
Virtual screening
Binding Sites
MESH: Humans
Organic Chemistry
Active site
Molecular biology
0104 chemical sciences
Enzyme Activation
010404 medicinal & biomolecular chemistry
Enzyme
chemistry
MESH: Binding Sites
Docking (molecular)
biology.protein
Zdroj: ChemMedChem
ChemMedChem, Wiley-VCH Verlag, 2011, 6 (10), pp.1797-805. ⟨10.1002/cmdc.201100281⟩
ChemMedChem, 2011, 6 (10), pp.1797-805. ⟨10.1002/cmdc.201100281⟩
6 (2011): 1797–1805. doi:10.1002/cmdc.201100281
info:cnr-pdr/source/autori:Ragno R, Gioia U, Laneve P, Bozzoni I, Mai A, Caffarelli E./titolo:Identification of Small-Molecule Inhibitors of the XendoU Endoribonucleases Family/doi:10.1002%2Fcmdc.201100281/rivista:ChemMedChem (Print)/anno:2011/pagina_da:1797/pagina_a:1805/intervallo_pagine:1797–1805/volume:6
Chemmedchem
ISSN: 1860-7179
1860-7187
DOI: 10.1002/cmdc.201100281⟩
Popis: The XendoU family of enzymes includes several proteins displaying high sequence homology. The members characterized so far are endoribonucleases sharing similar biochemical properties and a common architecture in their active sites. Despite their similarities, these proteins are involved in distinct RNA‐processing pathways in different organisms. The amphibian XendoU participates in the biosynthesis of small nucleolar RNAs, the human PP11 is supposed to play specialized roles in placental tissue, and NendoU has critical function in coronavirus replication. Notably, XendoU family members have been implicated in human pathologies such as cancer and respiratory diseases: PP11 is aberrantly expressed in various tumors, while NendoU activity has been associated with respiratory infections by pathogenic coronaviruses. The present study is aimed at identifying small molecules that may selectively interfere with these enzymatic activities. Combining structure‐based virtual screening and experimental approaches, we identified four molecules that specifically inhibited the catalytic activity of XendoU and PP11 in the low micromolar range. Moreover, docking experiments strongly suggested that these compounds might also bind to the active site of NendoU, thus impairing the catalytic activity essential for the coronavirus life cycle. The identified compounds, while allowing deep investigation of the molecular functions of this enzyme family, may also represent leads for the development of new therapeutic tools.
Dock, dock, docking! Using a combination of structure‐based and experimental approaches, we identified four inhibitors of the catalytic activity of XendoU RNases, a family of enzymes implicated in a range of diseases. A pharmacophore model is proposed, highlighting the chemical properties potentially required for efficient binding to XendoU.WILEY-VCHThis article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
Databáze: OpenAIRE
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