Cargando…
The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs
The coronavirus disease 2019 (COVID-19) represents a global public health burden. In addition to vaccination, safe and efficient antiviral treatment strategies to restrict the viral spread within the patient are urgently needed. An alternative approach to a single-drug therapy is the combinatory use...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9506552/ https://www.ncbi.nlm.nih.gov/pubmed/36145524 http://dx.doi.org/10.3390/pharmaceutics14091776 |
_version_ | 1784796751262121984 |
---|---|
author | Schreiber, André Ambrosy, Benjamin Planz, Oliver Schloer, Sebastian Rescher, Ursula Ludwig, Stephan |
author_facet | Schreiber, André Ambrosy, Benjamin Planz, Oliver Schloer, Sebastian Rescher, Ursula Ludwig, Stephan |
author_sort | Schreiber, André |
collection | PubMed |
description | The coronavirus disease 2019 (COVID-19) represents a global public health burden. In addition to vaccination, safe and efficient antiviral treatment strategies to restrict the viral spread within the patient are urgently needed. An alternative approach to a single-drug therapy is the combinatory use of virus- and host-targeted antivirals, leading to a synergistic boost of the drugs’ impact. In this study, we investigated the property of the MEK1/2 inhibitor ATR-002’s (zapnometinib) ability to potentiate the effect of direct-acting antivirals (DAA) against SARS-CoV-2 on viral replication. Treatment combinations of ATR-002 with nucleoside inhibitors Molnupiravir and Remdesivir or 3C-like protease inhibitors Nirmatrelvir and Ritonavir, the ingredients of the drug Paxlovid, were examined in Calu-3 cells to evaluate the advantage of their combinatory use against a SARS-CoV-2 infection. Synergistic effects could be observed for all tested combinations of ATR-002 with DAAs, as calculated by four different reference models in a concentration range that was very well-tolerated by the cells. Our results show that ATR-002 has the potential to act synergistically in combination with direct-acting antivirals, allowing for a reduction in the effective concentrations of the individual drugs and reducing side effects. |
format | Online Article Text |
id | pubmed-9506552 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95065522022-09-24 The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs Schreiber, André Ambrosy, Benjamin Planz, Oliver Schloer, Sebastian Rescher, Ursula Ludwig, Stephan Pharmaceutics Communication The coronavirus disease 2019 (COVID-19) represents a global public health burden. In addition to vaccination, safe and efficient antiviral treatment strategies to restrict the viral spread within the patient are urgently needed. An alternative approach to a single-drug therapy is the combinatory use of virus- and host-targeted antivirals, leading to a synergistic boost of the drugs’ impact. In this study, we investigated the property of the MEK1/2 inhibitor ATR-002’s (zapnometinib) ability to potentiate the effect of direct-acting antivirals (DAA) against SARS-CoV-2 on viral replication. Treatment combinations of ATR-002 with nucleoside inhibitors Molnupiravir and Remdesivir or 3C-like protease inhibitors Nirmatrelvir and Ritonavir, the ingredients of the drug Paxlovid, were examined in Calu-3 cells to evaluate the advantage of their combinatory use against a SARS-CoV-2 infection. Synergistic effects could be observed for all tested combinations of ATR-002 with DAAs, as calculated by four different reference models in a concentration range that was very well-tolerated by the cells. Our results show that ATR-002 has the potential to act synergistically in combination with direct-acting antivirals, allowing for a reduction in the effective concentrations of the individual drugs and reducing side effects. MDPI 2022-08-25 /pmc/articles/PMC9506552/ /pubmed/36145524 http://dx.doi.org/10.3390/pharmaceutics14091776 Text en © 2022 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 | Communication Schreiber, André Ambrosy, Benjamin Planz, Oliver Schloer, Sebastian Rescher, Ursula Ludwig, Stephan The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs |
title | The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs |
title_full | The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs |
title_fullStr | The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs |
title_full_unstemmed | The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs |
title_short | The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs |
title_sort | mek1/2 inhibitor atr-002 (zapnometinib) synergistically potentiates the antiviral effect of direct-acting anti-sars-cov-2 drugs |
topic | Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9506552/ https://www.ncbi.nlm.nih.gov/pubmed/36145524 http://dx.doi.org/10.3390/pharmaceutics14091776 |
work_keys_str_mv | AT schreiberandre themek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs AT ambrosybenjamin themek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs AT planzoliver themek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs AT schloersebastian themek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs AT rescherursula themek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs AT ludwigstephan themek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs AT schreiberandre mek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs AT ambrosybenjamin mek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs AT planzoliver mek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs AT schloersebastian mek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs AT rescherursula mek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs AT ludwigstephan mek12inhibitoratr002zapnometinibsynergisticallypotentiatestheantiviraleffectofdirectactingantisarscov2drugs |