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Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease

In cystic fibrosis (CF), the accumulation of viscous lung secretions rich in DNA and actin is a major cause of chronic inflammation and recurrent infections leading to airway obstruction. Mucolytic therapy based on recombinant human DNase1 reduces CF mucus viscosity and promotes airway clearance. Ho...

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Autores principales: Delfino, Danila, Mori, Giulia, Rivetti, Claudio, Grigoletto, Antonella, Bizzotto, Gloria, Cavozzi, Cristian, Malatesta, Marco, Cavazzini, Davide, Pasut, Gianfranco, Percudani, Riccardo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002113/
https://www.ncbi.nlm.nih.gov/pubmed/33802146
http://dx.doi.org/10.3390/biom11030410
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author Delfino, Danila
Mori, Giulia
Rivetti, Claudio
Grigoletto, Antonella
Bizzotto, Gloria
Cavozzi, Cristian
Malatesta, Marco
Cavazzini, Davide
Pasut, Gianfranco
Percudani, Riccardo
author_facet Delfino, Danila
Mori, Giulia
Rivetti, Claudio
Grigoletto, Antonella
Bizzotto, Gloria
Cavozzi, Cristian
Malatesta, Marco
Cavazzini, Davide
Pasut, Gianfranco
Percudani, Riccardo
author_sort Delfino, Danila
collection PubMed
description In cystic fibrosis (CF), the accumulation of viscous lung secretions rich in DNA and actin is a major cause of chronic inflammation and recurrent infections leading to airway obstruction. Mucolytic therapy based on recombinant human DNase1 reduces CF mucus viscosity and promotes airway clearance. However, the marked susceptibility to actin inhibition of this enzyme prompts the research of alternative treatments that could overcome this limitation. Within the human DNase repertoire, DNase1L2 is ideally suited for this purpose because it exhibits metal-dependent endonuclease activity on plasmid DNA in a broad range of pH with acidic optimum and is minimally inhibited by actin. When tested on CF artificial mucus enriched with actin, submicromolar concentrations of DNase1L2 reduces mucus viscosity by 50% in a few seconds. Inspection of superimposed model structures of DNase1 and DNase1L2 highlights differences at the actin-binding interface that justify the increased resistance of DNase1L2 toward actin inhibition. Furthermore, a PEGylated form of the enzyme with preserved enzymatic activity was obtained, showing interesting results in terms of activity. This work represents an effort toward the exploitation of natural DNase variants as promising alternatives to DNase1 for the treatment of CF lung disease.
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spelling pubmed-80021132021-03-28 Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease Delfino, Danila Mori, Giulia Rivetti, Claudio Grigoletto, Antonella Bizzotto, Gloria Cavozzi, Cristian Malatesta, Marco Cavazzini, Davide Pasut, Gianfranco Percudani, Riccardo Biomolecules Article In cystic fibrosis (CF), the accumulation of viscous lung secretions rich in DNA and actin is a major cause of chronic inflammation and recurrent infections leading to airway obstruction. Mucolytic therapy based on recombinant human DNase1 reduces CF mucus viscosity and promotes airway clearance. However, the marked susceptibility to actin inhibition of this enzyme prompts the research of alternative treatments that could overcome this limitation. Within the human DNase repertoire, DNase1L2 is ideally suited for this purpose because it exhibits metal-dependent endonuclease activity on plasmid DNA in a broad range of pH with acidic optimum and is minimally inhibited by actin. When tested on CF artificial mucus enriched with actin, submicromolar concentrations of DNase1L2 reduces mucus viscosity by 50% in a few seconds. Inspection of superimposed model structures of DNase1 and DNase1L2 highlights differences at the actin-binding interface that justify the increased resistance of DNase1L2 toward actin inhibition. Furthermore, a PEGylated form of the enzyme with preserved enzymatic activity was obtained, showing interesting results in terms of activity. This work represents an effort toward the exploitation of natural DNase variants as promising alternatives to DNase1 for the treatment of CF lung disease. MDPI 2021-03-10 /pmc/articles/PMC8002113/ /pubmed/33802146 http://dx.doi.org/10.3390/biom11030410 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Delfino, Danila
Mori, Giulia
Rivetti, Claudio
Grigoletto, Antonella
Bizzotto, Gloria
Cavozzi, Cristian
Malatesta, Marco
Cavazzini, Davide
Pasut, Gianfranco
Percudani, Riccardo
Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease
title Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease
title_full Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease
title_fullStr Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease
title_full_unstemmed Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease
title_short Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease
title_sort actin-resistant dnase1l2 as a potential therapeutics for cf lung disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002113/
https://www.ncbi.nlm.nih.gov/pubmed/33802146
http://dx.doi.org/10.3390/biom11030410
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