Cargando…

Differential Efficacy of Novel Antiviral Substances in 3D and Monolayer Cell Culture

Repurposing of approved drugs that target host functions also important for virus replication promises to overcome the shortage of antiviral therapeutics. Mostly, virus biology including initial screening of antivirals is studied in conventional monolayer cells. The biology of these cells differs co...

Descripción completa

Detalles Bibliográficos
Autores principales: Koban, Robert, Neumann, Markus, Nelson, Philipp P., Ellerbrok, Heinz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697553/
https://www.ncbi.nlm.nih.gov/pubmed/33198108
http://dx.doi.org/10.3390/v12111294
_version_ 1783615622713704448
author Koban, Robert
Neumann, Markus
Nelson, Philipp P.
Ellerbrok, Heinz
author_facet Koban, Robert
Neumann, Markus
Nelson, Philipp P.
Ellerbrok, Heinz
author_sort Koban, Robert
collection PubMed
description Repurposing of approved drugs that target host functions also important for virus replication promises to overcome the shortage of antiviral therapeutics. Mostly, virus biology including initial screening of antivirals is studied in conventional monolayer cells. The biology of these cells differs considerably from infected tissues. 3D culture models with characteristics of human tissues may reflect more realistically the in vivo events during infection. We screened first, second, and third generation epidermal growth factor receptor (EGFR)-inhibitors with different modes of action and the EGFR-blocking monoclonal antibody cetuximab in a 3D cell culture infection model with primary human keratinocytes and cowpox virus (CPXV) for antiviral activity. Antiviral activity of erlotinib and osimertinib was nearly unaffected by the cultivation method similar to the virus-directed antivirals tecovirimat and cidofovir. In contrast, the host-directed inhibitors afatinib and cetuximab were approx. 100-fold more efficient against CPXV in the 3D infection model, similar to previous results with gefitinib. In summary, inhibition of EGFR-signaling downregulates virus replication comparable to established virus-directed antivirals. However, in contrast to virus-directed inhibitors, in vitro efficacy of host-directed antivirals might be seriously affected by cell cultivation. Results obtained for afatinib and cetuximab suggest that screening of such drugs in standard monolayer culture might underestimate their potential as antivirals.
format Online
Article
Text
id pubmed-7697553
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-76975532020-11-29 Differential Efficacy of Novel Antiviral Substances in 3D and Monolayer Cell Culture Koban, Robert Neumann, Markus Nelson, Philipp P. Ellerbrok, Heinz Viruses Article Repurposing of approved drugs that target host functions also important for virus replication promises to overcome the shortage of antiviral therapeutics. Mostly, virus biology including initial screening of antivirals is studied in conventional monolayer cells. The biology of these cells differs considerably from infected tissues. 3D culture models with characteristics of human tissues may reflect more realistically the in vivo events during infection. We screened first, second, and third generation epidermal growth factor receptor (EGFR)-inhibitors with different modes of action and the EGFR-blocking monoclonal antibody cetuximab in a 3D cell culture infection model with primary human keratinocytes and cowpox virus (CPXV) for antiviral activity. Antiviral activity of erlotinib and osimertinib was nearly unaffected by the cultivation method similar to the virus-directed antivirals tecovirimat and cidofovir. In contrast, the host-directed inhibitors afatinib and cetuximab were approx. 100-fold more efficient against CPXV in the 3D infection model, similar to previous results with gefitinib. In summary, inhibition of EGFR-signaling downregulates virus replication comparable to established virus-directed antivirals. However, in contrast to virus-directed inhibitors, in vitro efficacy of host-directed antivirals might be seriously affected by cell cultivation. Results obtained for afatinib and cetuximab suggest that screening of such drugs in standard monolayer culture might underestimate their potential as antivirals. MDPI 2020-11-12 /pmc/articles/PMC7697553/ /pubmed/33198108 http://dx.doi.org/10.3390/v12111294 Text en © 2020 by the authors. 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/).
spellingShingle Article
Koban, Robert
Neumann, Markus
Nelson, Philipp P.
Ellerbrok, Heinz
Differential Efficacy of Novel Antiviral Substances in 3D and Monolayer Cell Culture
title Differential Efficacy of Novel Antiviral Substances in 3D and Monolayer Cell Culture
title_full Differential Efficacy of Novel Antiviral Substances in 3D and Monolayer Cell Culture
title_fullStr Differential Efficacy of Novel Antiviral Substances in 3D and Monolayer Cell Culture
title_full_unstemmed Differential Efficacy of Novel Antiviral Substances in 3D and Monolayer Cell Culture
title_short Differential Efficacy of Novel Antiviral Substances in 3D and Monolayer Cell Culture
title_sort differential efficacy of novel antiviral substances in 3d and monolayer cell culture
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697553/
https://www.ncbi.nlm.nih.gov/pubmed/33198108
http://dx.doi.org/10.3390/v12111294
work_keys_str_mv AT kobanrobert differentialefficacyofnovelantiviralsubstancesin3dandmonolayercellculture
AT neumannmarkus differentialefficacyofnovelantiviralsubstancesin3dandmonolayercellculture
AT nelsonphilippp differentialefficacyofnovelantiviralsubstancesin3dandmonolayercellculture
AT ellerbrokheinz differentialefficacyofnovelantiviralsubstancesin3dandmonolayercellculture