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In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camos...

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Autores principales: Hassan, Ahmed H. E., El-Sayed, Selwan M., Yamamoto, Mizuki, Gohda, Jin, Matsumoto, Takehisa, Shirouzu, Mikako, Inoue, Jun-ichiro, Kawaguchi, Yasushi, Mansour, Reem M. A., Anvari, Abtin, Farahat, Abdelbasset A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10223987/
https://www.ncbi.nlm.nih.gov/pubmed/37243257
http://dx.doi.org/10.3390/v15051171
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author Hassan, Ahmed H. E.
El-Sayed, Selwan M.
Yamamoto, Mizuki
Gohda, Jin
Matsumoto, Takehisa
Shirouzu, Mikako
Inoue, Jun-ichiro
Kawaguchi, Yasushi
Mansour, Reem M. A.
Anvari, Abtin
Farahat, Abdelbasset A.
author_facet Hassan, Ahmed H. E.
El-Sayed, Selwan M.
Yamamoto, Mizuki
Gohda, Jin
Matsumoto, Takehisa
Shirouzu, Mikako
Inoue, Jun-ichiro
Kawaguchi, Yasushi
Mansour, Reem M. A.
Anvari, Abtin
Farahat, Abdelbasset A.
author_sort Hassan, Ahmed H. E.
collection PubMed
description Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent inhibitors of TMPRSS2 protease involved in viral entry. To circumvent their limitations, a reversible inhibitor might be required. Considering nafamostat structure and using pentamidine as a starting point, a small set of structurally diverse rigid analogues were designed and evaluated in silico to guide selection of compounds to be prepared for biological evaluation. Based on the results of in silico study, six compounds were prepared and evaluated in vitro. At the enzyme level, compounds 10–12 triggered potential TMPRSS2 inhibition with low micromolar IC(50) concentrations, but they were less effective in cellular assays. Meanwhile, compound 14 did not trigger potential TMPRSS2 inhibition at the enzyme level, but it showed potential cellular activity regarding inhibition of membrane fusion with a low micromolar IC(50) value of 10.87 µM, suggesting its action could be mediated by another molecular target. Furthermore, in vitro evaluation showed that compound 14 inhibited pseudovirus entry as well as thrombin and factor Xa. Together, this study presents compound 14 as a hit compound that might serve as a starting point for developing potential viral entry inhibitors with possible application against coronaviruses.
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spelling pubmed-102239872023-05-28 In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases Hassan, Ahmed H. E. El-Sayed, Selwan M. Yamamoto, Mizuki Gohda, Jin Matsumoto, Takehisa Shirouzu, Mikako Inoue, Jun-ichiro Kawaguchi, Yasushi Mansour, Reem M. A. Anvari, Abtin Farahat, Abdelbasset A. Viruses Article Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent inhibitors of TMPRSS2 protease involved in viral entry. To circumvent their limitations, a reversible inhibitor might be required. Considering nafamostat structure and using pentamidine as a starting point, a small set of structurally diverse rigid analogues were designed and evaluated in silico to guide selection of compounds to be prepared for biological evaluation. Based on the results of in silico study, six compounds were prepared and evaluated in vitro. At the enzyme level, compounds 10–12 triggered potential TMPRSS2 inhibition with low micromolar IC(50) concentrations, but they were less effective in cellular assays. Meanwhile, compound 14 did not trigger potential TMPRSS2 inhibition at the enzyme level, but it showed potential cellular activity regarding inhibition of membrane fusion with a low micromolar IC(50) value of 10.87 µM, suggesting its action could be mediated by another molecular target. Furthermore, in vitro evaluation showed that compound 14 inhibited pseudovirus entry as well as thrombin and factor Xa. Together, this study presents compound 14 as a hit compound that might serve as a starting point for developing potential viral entry inhibitors with possible application against coronaviruses. MDPI 2023-05-15 /pmc/articles/PMC10223987/ /pubmed/37243257 http://dx.doi.org/10.3390/v15051171 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
Hassan, Ahmed H. E.
El-Sayed, Selwan M.
Yamamoto, Mizuki
Gohda, Jin
Matsumoto, Takehisa
Shirouzu, Mikako
Inoue, Jun-ichiro
Kawaguchi, Yasushi
Mansour, Reem M. A.
Anvari, Abtin
Farahat, Abdelbasset A.
In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases
title In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases
title_full In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases
title_fullStr In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases
title_full_unstemmed In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases
title_short In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases
title_sort in silico and in vitro evaluation of some amidine derivatives as hit compounds towards development of inhibitors against coronavirus diseases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10223987/
https://www.ncbi.nlm.nih.gov/pubmed/37243257
http://dx.doi.org/10.3390/v15051171
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