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Exploration of Novel Scaffolds Targeting Cytochrome b of Pyricularia oryzae

The fulfilment of the European “Farm to Fork” strategy requires a drastic reduction in the use of “at risk” synthetic pesticides; this exposes vulnerable agricultural sectors—among which is the European risiculture—to the lack of efficient means for the management of devastating diseases, thus endan...

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Autores principales: Pinna, Cecilia, Laurenzi, Tommaso, Forlani, Fabio, Palazzolo, Luca, Nolan, Claire Beatrice, Christodoulou, Michael S., Cortesi, Paolo, Pinto, Andrea, Eberini, Ivano, Kunova, Andrea, Dallavalle, Sabrina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917009/
https://www.ncbi.nlm.nih.gov/pubmed/36769028
http://dx.doi.org/10.3390/ijms24032705
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author Pinna, Cecilia
Laurenzi, Tommaso
Forlani, Fabio
Palazzolo, Luca
Nolan, Claire Beatrice
Christodoulou, Michael S.
Cortesi, Paolo
Pinto, Andrea
Eberini, Ivano
Kunova, Andrea
Dallavalle, Sabrina
author_facet Pinna, Cecilia
Laurenzi, Tommaso
Forlani, Fabio
Palazzolo, Luca
Nolan, Claire Beatrice
Christodoulou, Michael S.
Cortesi, Paolo
Pinto, Andrea
Eberini, Ivano
Kunova, Andrea
Dallavalle, Sabrina
author_sort Pinna, Cecilia
collection PubMed
description The fulfilment of the European “Farm to Fork” strategy requires a drastic reduction in the use of “at risk” synthetic pesticides; this exposes vulnerable agricultural sectors—among which is the European risiculture—to the lack of efficient means for the management of devastating diseases, thus endangering food security. Therefore, novel scaffolds need to be identified for the synthesis of new and more environmentally friendly fungicides. In the present work, we employed our previously developed 3D model of P. oryzae cytochrome bc1 (cyt bc1) complex to perform a high-throughput virtual screening of two commercially available compound libraries. Three chemotypes were selected, from which a small collection of differently substituted analogues was designed and synthesized. The compounds were tested as inhibitors of the cyt bc1 enzyme function and the mycelium growth of both strobilurin-sensitive (WT) and -resistant (RES) P. oryzae strains. This pipeline has permitted the identification of thirteen compounds active against the RES cyt bc1 and five compounds that inhibited the WT cyt bc1 function while inhibiting the fungal mycelia only minimally. Serendipitously, among the studied compounds we identified a new chemotype that is able to efficiently inhibit the mycelium growth of WT and RES strains by ca. 60%, without inhibiting the cyt bc1 enzymatic function, suggesting a different mechanism of action.
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spelling pubmed-99170092023-02-11 Exploration of Novel Scaffolds Targeting Cytochrome b of Pyricularia oryzae Pinna, Cecilia Laurenzi, Tommaso Forlani, Fabio Palazzolo, Luca Nolan, Claire Beatrice Christodoulou, Michael S. Cortesi, Paolo Pinto, Andrea Eberini, Ivano Kunova, Andrea Dallavalle, Sabrina Int J Mol Sci Article The fulfilment of the European “Farm to Fork” strategy requires a drastic reduction in the use of “at risk” synthetic pesticides; this exposes vulnerable agricultural sectors—among which is the European risiculture—to the lack of efficient means for the management of devastating diseases, thus endangering food security. Therefore, novel scaffolds need to be identified for the synthesis of new and more environmentally friendly fungicides. In the present work, we employed our previously developed 3D model of P. oryzae cytochrome bc1 (cyt bc1) complex to perform a high-throughput virtual screening of two commercially available compound libraries. Three chemotypes were selected, from which a small collection of differently substituted analogues was designed and synthesized. The compounds were tested as inhibitors of the cyt bc1 enzyme function and the mycelium growth of both strobilurin-sensitive (WT) and -resistant (RES) P. oryzae strains. This pipeline has permitted the identification of thirteen compounds active against the RES cyt bc1 and five compounds that inhibited the WT cyt bc1 function while inhibiting the fungal mycelia only minimally. Serendipitously, among the studied compounds we identified a new chemotype that is able to efficiently inhibit the mycelium growth of WT and RES strains by ca. 60%, without inhibiting the cyt bc1 enzymatic function, suggesting a different mechanism of action. MDPI 2023-01-31 /pmc/articles/PMC9917009/ /pubmed/36769028 http://dx.doi.org/10.3390/ijms24032705 Text en © 2023 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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pinna, Cecilia
Laurenzi, Tommaso
Forlani, Fabio
Palazzolo, Luca
Nolan, Claire Beatrice
Christodoulou, Michael S.
Cortesi, Paolo
Pinto, Andrea
Eberini, Ivano
Kunova, Andrea
Dallavalle, Sabrina
Exploration of Novel Scaffolds Targeting Cytochrome b of Pyricularia oryzae
title Exploration of Novel Scaffolds Targeting Cytochrome b of Pyricularia oryzae
title_full Exploration of Novel Scaffolds Targeting Cytochrome b of Pyricularia oryzae
title_fullStr Exploration of Novel Scaffolds Targeting Cytochrome b of Pyricularia oryzae
title_full_unstemmed Exploration of Novel Scaffolds Targeting Cytochrome b of Pyricularia oryzae
title_short Exploration of Novel Scaffolds Targeting Cytochrome b of Pyricularia oryzae
title_sort exploration of novel scaffolds targeting cytochrome b of pyricularia oryzae
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917009/
https://www.ncbi.nlm.nih.gov/pubmed/36769028
http://dx.doi.org/10.3390/ijms24032705
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