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Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection

[Image: see text] The urgency to find complementary therapies to current SARS-CoV-2 vaccines, whose effectiveness is preserved over time and not compromised by the emergence of new and emerging variants, has become a critical health challenge. We investigate the possibility of jamming the opening of...

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Autores principales: Stagnoli, Soledad, Macari, Gabriele, Corsi, Pietro, Capone, Barbara, Vidaurrazaga, Ander, Ereño-Orbea, June, Ardá, Ana, Polticelli, Fabio, Jiménez-Barbero, Jesús, Abrescia, Nicola GA, Coluzza, Ivan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10666140/
https://www.ncbi.nlm.nih.gov/pubmed/38027314
http://dx.doi.org/10.1021/acsomega.3c02921
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author Stagnoli, Soledad
Macari, Gabriele
Corsi, Pietro
Capone, Barbara
Vidaurrazaga, Ander
Ereño-Orbea, June
Ardá, Ana
Polticelli, Fabio
Jiménez-Barbero, Jesús
Abrescia, Nicola GA
Coluzza, Ivan
author_facet Stagnoli, Soledad
Macari, Gabriele
Corsi, Pietro
Capone, Barbara
Vidaurrazaga, Ander
Ereño-Orbea, June
Ardá, Ana
Polticelli, Fabio
Jiménez-Barbero, Jesús
Abrescia, Nicola GA
Coluzza, Ivan
author_sort Stagnoli, Soledad
collection PubMed
description [Image: see text] The urgency to find complementary therapies to current SARS-CoV-2 vaccines, whose effectiveness is preserved over time and not compromised by the emergence of new and emerging variants, has become a critical health challenge. We investigate the possibility of jamming the opening of the Receptor Binding Domain (RBD) of the spike protein of SARS-CoV-2 with small compounds. Through in silico screening, we identified two potential candidates that would lock the Receptor Binding Domain (RBD) in a closed configuration, preventing the virus from infecting the host cells. We show that two drugs already approved by the FDA, mithramycin and dihydroergotamine, can block infection using concentrations in the μM range in cell-based assays. Further STD-NMR experiments support dihydroergotamine’s direct interaction with the spike protein. Overall, our results indicate that repurposing of these compounds might lead to potential clinical drug candidates for the treatment of SARS-CoV-2 infection.
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spelling pubmed-106661402023-11-13 Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection Stagnoli, Soledad Macari, Gabriele Corsi, Pietro Capone, Barbara Vidaurrazaga, Ander Ereño-Orbea, June Ardá, Ana Polticelli, Fabio Jiménez-Barbero, Jesús Abrescia, Nicola GA Coluzza, Ivan ACS Omega [Image: see text] The urgency to find complementary therapies to current SARS-CoV-2 vaccines, whose effectiveness is preserved over time and not compromised by the emergence of new and emerging variants, has become a critical health challenge. We investigate the possibility of jamming the opening of the Receptor Binding Domain (RBD) of the spike protein of SARS-CoV-2 with small compounds. Through in silico screening, we identified two potential candidates that would lock the Receptor Binding Domain (RBD) in a closed configuration, preventing the virus from infecting the host cells. We show that two drugs already approved by the FDA, mithramycin and dihydroergotamine, can block infection using concentrations in the μM range in cell-based assays. Further STD-NMR experiments support dihydroergotamine’s direct interaction with the spike protein. Overall, our results indicate that repurposing of these compounds might lead to potential clinical drug candidates for the treatment of SARS-CoV-2 infection. American Chemical Society 2023-11-13 /pmc/articles/PMC10666140/ /pubmed/38027314 http://dx.doi.org/10.1021/acsomega.3c02921 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Stagnoli, Soledad
Macari, Gabriele
Corsi, Pietro
Capone, Barbara
Vidaurrazaga, Ander
Ereño-Orbea, June
Ardá, Ana
Polticelli, Fabio
Jiménez-Barbero, Jesús
Abrescia, Nicola GA
Coluzza, Ivan
Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection
title Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection
title_full Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection
title_fullStr Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection
title_full_unstemmed Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection
title_short Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection
title_sort targeting the spike: repurposing mithramycin and dihydroergotamine to block sars-cov-2 infection
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10666140/
https://www.ncbi.nlm.nih.gov/pubmed/38027314
http://dx.doi.org/10.1021/acsomega.3c02921
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