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Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors

[Image: see text] Finding antivirals for SARS-CoV-2 is still a major challenge, and many computational and experimental approaches have been employed to find a solution to this problem. While the global vaccination campaigns are the primary driver of controlling the current pandemic, orally bioavail...

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Autores principales: Puhl, Ana C., Mottin, Melina, Sacramento, Carolina Q., Tavella, Tatyana Almeida, Dias, Gabriel Gonçalves, Fintelman-Rodrigues, Natalia, Temerozo, Jairo R., Dias, Suelen S. G., Ramos, Paulo Ricardo Pimenta da Silva, Merten, Eric M., Pearce, Kenneth H., Costa, Fabio Trindade Maranhão, Premkumar, Lakshmanane, Souza, Thiago Moreno L., Andrade, Carolina Horta, Ekins, Sean
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380819/
https://www.ncbi.nlm.nih.gov/pubmed/35983371
http://dx.doi.org/10.1021/acsomega.2c01707
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author Puhl, Ana C.
Mottin, Melina
Sacramento, Carolina Q.
Tavella, Tatyana Almeida
Dias, Gabriel Gonçalves
Fintelman-Rodrigues, Natalia
Temerozo, Jairo R.
Dias, Suelen S. G.
Ramos, Paulo Ricardo Pimenta da Silva
Merten, Eric M.
Pearce, Kenneth H.
Costa, Fabio Trindade Maranhão
Premkumar, Lakshmanane
Souza, Thiago Moreno L.
Andrade, Carolina Horta
Ekins, Sean
author_facet Puhl, Ana C.
Mottin, Melina
Sacramento, Carolina Q.
Tavella, Tatyana Almeida
Dias, Gabriel Gonçalves
Fintelman-Rodrigues, Natalia
Temerozo, Jairo R.
Dias, Suelen S. G.
Ramos, Paulo Ricardo Pimenta da Silva
Merten, Eric M.
Pearce, Kenneth H.
Costa, Fabio Trindade Maranhão
Premkumar, Lakshmanane
Souza, Thiago Moreno L.
Andrade, Carolina Horta
Ekins, Sean
author_sort Puhl, Ana C.
collection PubMed
description [Image: see text] Finding antivirals for SARS-CoV-2 is still a major challenge, and many computational and experimental approaches have been employed to find a solution to this problem. While the global vaccination campaigns are the primary driver of controlling the current pandemic, orally bioavailable small-molecule drugs and biologics are critical to overcome this global issue. Improved therapeutics and prophylactics are required to treat people with circulating and emerging new variants, addressing severe infection, and people with underlying or immunocompromised conditions. The SARS-CoV-2 envelope spike is a challenging target for viral entry inhibitors. Pindolol presented a good docking score in a previous virtual screening using computational docking calculations after screening a Food and Drug Administration (FDA)-approved drug library of 2400 molecules as potential candidates to block the SARS-CoV-2 spike protein interaction with the angiotensin-converting enzyme 2 (ACE-2). Here, we expanded the computational evaluation to identify five beta-blockers against SARS-CoV-2 using several techniques, such as microscale thermophoresis, NanoDSF, and in vitro assays in different cell lines. These data identified carvedilol with a K(d) of 364 ± 22 nM for the SARS-CoV-2 spike and in vitro activity (EC(50) of 7.57 μM, CC(50) of 18.07 μM) against SARS-CoV-2 in Calu-3 cells. We have shown how we can apply multiple computational and experimental approaches to find molecules that can be further optimized to improve anti-SARS-CoV-2 activity.
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spelling pubmed-93808192022-08-16 Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors Puhl, Ana C. Mottin, Melina Sacramento, Carolina Q. Tavella, Tatyana Almeida Dias, Gabriel Gonçalves Fintelman-Rodrigues, Natalia Temerozo, Jairo R. Dias, Suelen S. G. Ramos, Paulo Ricardo Pimenta da Silva Merten, Eric M. Pearce, Kenneth H. Costa, Fabio Trindade Maranhão Premkumar, Lakshmanane Souza, Thiago Moreno L. Andrade, Carolina Horta Ekins, Sean ACS Omega [Image: see text] Finding antivirals for SARS-CoV-2 is still a major challenge, and many computational and experimental approaches have been employed to find a solution to this problem. While the global vaccination campaigns are the primary driver of controlling the current pandemic, orally bioavailable small-molecule drugs and biologics are critical to overcome this global issue. Improved therapeutics and prophylactics are required to treat people with circulating and emerging new variants, addressing severe infection, and people with underlying or immunocompromised conditions. The SARS-CoV-2 envelope spike is a challenging target for viral entry inhibitors. Pindolol presented a good docking score in a previous virtual screening using computational docking calculations after screening a Food and Drug Administration (FDA)-approved drug library of 2400 molecules as potential candidates to block the SARS-CoV-2 spike protein interaction with the angiotensin-converting enzyme 2 (ACE-2). Here, we expanded the computational evaluation to identify five beta-blockers against SARS-CoV-2 using several techniques, such as microscale thermophoresis, NanoDSF, and in vitro assays in different cell lines. These data identified carvedilol with a K(d) of 364 ± 22 nM for the SARS-CoV-2 spike and in vitro activity (EC(50) of 7.57 μM, CC(50) of 18.07 μM) against SARS-CoV-2 in Calu-3 cells. We have shown how we can apply multiple computational and experimental approaches to find molecules that can be further optimized to improve anti-SARS-CoV-2 activity. American Chemical Society 2022-08-08 /pmc/articles/PMC9380819/ /pubmed/35983371 http://dx.doi.org/10.1021/acsomega.2c01707 Text en © 2022 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 Puhl, Ana C.
Mottin, Melina
Sacramento, Carolina Q.
Tavella, Tatyana Almeida
Dias, Gabriel Gonçalves
Fintelman-Rodrigues, Natalia
Temerozo, Jairo R.
Dias, Suelen S. G.
Ramos, Paulo Ricardo Pimenta da Silva
Merten, Eric M.
Pearce, Kenneth H.
Costa, Fabio Trindade Maranhão
Premkumar, Lakshmanane
Souza, Thiago Moreno L.
Andrade, Carolina Horta
Ekins, Sean
Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors
title Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors
title_full Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors
title_fullStr Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors
title_full_unstemmed Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors
title_short Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors
title_sort computational and experimental approaches identify beta-blockers as potential sars-cov-2 spike inhibitors
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380819/
https://www.ncbi.nlm.nih.gov/pubmed/35983371
http://dx.doi.org/10.1021/acsomega.2c01707
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