Novel Nonnucleoside Inhibitors of Zika Virus Polymerase Identified through the Screening of an Open Library of Antikinetoplastid Compounds
Zika virus (ZIKV) is a mosquito-borne pathogen responsible for neurological disorders (Guillain-Barre syndrome) and congenital malformations (microcephaly). Its ability to cause explosive epidemics, such as that of 2015 to 2016, urges the identification of effective antiviral drugs. Viral polymerase inhibitors constitute one of the most successful fields in antiviral research. Accordingly, the RNA-dependent RNA polymerase activity of flavivirus nonstructural protein 5 (NS5) provides a unique target for the development of direct antivirals with high specificity and low toxicity. Here, we describe the discovery and characterization of two novel nonnucleoside inhibitors of ZIKV polymerase. These inhibitors, TCMDC-143406 (compound 6) and TCMDC-143215 (compound 15) were identified through the screening of an open-resource library of antikinetoplastid compounds using a fluorescence-based polymerization assay based on ZIKV NS5. The two compounds inhibited ZIKV NS5 polymerase activity in vitro and ZIKV multiplication in cell culture (half-maximal effective concentrations (EC50] values of 0.5 and 2.6 mu M for compounds 6 and 15, respectively). Both compounds also inhibited the replication of other pathogenic flaviviruses, namely, West Nile virus (WNV; EC50 values of 4.3 and 4.6 mu M for compounds 6 and 15, respectively) and dengue virus 2 (DENV-2; EC50 values of 3.4 and 9.6 mu M for compounds 6 and 15, respectively). Enzymatic assays confirmed that the polymerase inhibition was produced by a noncompetitive mechanism. Combinatorial assays revealed an antagonistic effect between both compounds, suggesting that they would bind to the same region of ZIKV polymerase. The nonnucleoside inhibitors of ZIKV polymerase here described could constitute promising lead compounds for the development of anti-ZIKV therapies and, eventually, broad-spectrum antiflavivirus drugs.
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Format: | artículo biblioteca |
Language: | English |
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American Society for Microbiology
2021-08-17
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Subjects: | Zika virus, West Nile virus, Dengue virus, Polymerase, Nonnucleoside inhibitor, Allosteric, Antiviral, RNA polymerases, Antiviral agents, |
Online Access: | http://hdl.handle.net/20.500.12792/6157 http://hdl.handle.net/10261/289827 |
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dig-inia-es-10261-2898272023-02-17T08:24:20Z Novel Nonnucleoside Inhibitors of Zika Virus Polymerase Identified through the Screening of an Open Library of Antikinetoplastid Compounds Jiménez De Oya, Nereida Saiz Calahorra, Juan Carlos Martín-Acebes, M. A. Del Aguila, Carmen Arias, Armando Agudo, Ruben Saez-Alvarez, Yanira Martín-Acebes, M. A. Zika virus West Nile virus Dengue virus Polymerase Nonnucleoside inhibitor Allosteric Antiviral RNA polymerases Antiviral agents Zika virus (ZIKV) is a mosquito-borne pathogen responsible for neurological disorders (Guillain-Barre syndrome) and congenital malformations (microcephaly). Its ability to cause explosive epidemics, such as that of 2015 to 2016, urges the identification of effective antiviral drugs. Viral polymerase inhibitors constitute one of the most successful fields in antiviral research. Accordingly, the RNA-dependent RNA polymerase activity of flavivirus nonstructural protein 5 (NS5) provides a unique target for the development of direct antivirals with high specificity and low toxicity. Here, we describe the discovery and characterization of two novel nonnucleoside inhibitors of ZIKV polymerase. These inhibitors, TCMDC-143406 (compound 6) and TCMDC-143215 (compound 15) were identified through the screening of an open-resource library of antikinetoplastid compounds using a fluorescence-based polymerization assay based on ZIKV NS5. The two compounds inhibited ZIKV NS5 polymerase activity in vitro and ZIKV multiplication in cell culture (half-maximal effective concentrations (EC50] values of 0.5 and 2.6 mu M for compounds 6 and 15, respectively). Both compounds also inhibited the replication of other pathogenic flaviviruses, namely, West Nile virus (WNV; EC50 values of 4.3 and 4.6 mu M for compounds 6 and 15, respectively) and dengue virus 2 (DENV-2; EC50 values of 3.4 and 9.6 mu M for compounds 6 and 15, respectively). Enzymatic assays confirmed that the polymerase inhibition was produced by a noncompetitive mechanism. Combinatorial assays revealed an antagonistic effect between both compounds, suggesting that they would bind to the same region of ZIKV polymerase. The nonnucleoside inhibitors of ZIKV polymerase here described could constitute promising lead compounds for the development of anti-ZIKV therapies and, eventually, broad-spectrum antiflavivirus drugs. 2023-02-17T08:24:20Z 2023-02-17T08:24:20Z 2021-08-17 artículo Antimicrobial Agents and Chemotherapy 65(9): e0089421 (2021) 0066-4804 http://hdl.handle.net/20.500.12792/6157 http://hdl.handle.net/10261/289827 10.1128/AAC.00894-21 1098-6596 en open American Society for Microbiology |
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Zika virus West Nile virus Dengue virus Polymerase Nonnucleoside inhibitor Allosteric Antiviral RNA polymerases Antiviral agents Zika virus West Nile virus Dengue virus Polymerase Nonnucleoside inhibitor Allosteric Antiviral RNA polymerases Antiviral agents |
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Zika virus West Nile virus Dengue virus Polymerase Nonnucleoside inhibitor Allosteric Antiviral RNA polymerases Antiviral agents Zika virus West Nile virus Dengue virus Polymerase Nonnucleoside inhibitor Allosteric Antiviral RNA polymerases Antiviral agents Jiménez De Oya, Nereida Saiz Calahorra, Juan Carlos Martín-Acebes, M. A. Del Aguila, Carmen Arias, Armando Agudo, Ruben Saez-Alvarez, Yanira Martín-Acebes, M. A. Novel Nonnucleoside Inhibitors of Zika Virus Polymerase Identified through the Screening of an Open Library of Antikinetoplastid Compounds |
description |
Zika virus (ZIKV) is a mosquito-borne pathogen responsible for neurological disorders (Guillain-Barre syndrome) and congenital malformations (microcephaly). Its ability to cause explosive epidemics, such as that of 2015 to 2016, urges the identification of effective antiviral drugs. Viral polymerase inhibitors constitute one of the most successful fields in antiviral research. Accordingly, the RNA-dependent RNA polymerase activity of flavivirus nonstructural protein 5 (NS5) provides a unique target for the development of direct antivirals with high specificity and low toxicity. Here, we describe the discovery and characterization of two novel nonnucleoside inhibitors of ZIKV polymerase. These inhibitors, TCMDC-143406 (compound 6) and TCMDC-143215 (compound 15) were identified through the screening of an open-resource library of antikinetoplastid compounds using a fluorescence-based polymerization assay based on ZIKV NS5. The two compounds inhibited ZIKV NS5 polymerase activity in vitro and ZIKV multiplication in cell culture (half-maximal effective concentrations (EC50] values of 0.5 and 2.6 mu M for compounds 6 and 15, respectively). Both compounds also inhibited the replication of other pathogenic flaviviruses, namely, West Nile virus (WNV; EC50 values of 4.3 and 4.6 mu M for compounds 6 and 15, respectively) and dengue virus 2 (DENV-2; EC50 values of 3.4 and 9.6 mu M for compounds 6 and 15, respectively). Enzymatic assays confirmed that the polymerase inhibition was produced by a noncompetitive mechanism. Combinatorial assays revealed an antagonistic effect between both compounds, suggesting that they would bind to the same region of ZIKV polymerase. The nonnucleoside inhibitors of ZIKV polymerase here described could constitute promising lead compounds for the development of anti-ZIKV therapies and, eventually, broad-spectrum antiflavivirus drugs. |
format |
artículo |
topic_facet |
Zika virus West Nile virus Dengue virus Polymerase Nonnucleoside inhibitor Allosteric Antiviral RNA polymerases Antiviral agents |
author |
Jiménez De Oya, Nereida Saiz Calahorra, Juan Carlos Martín-Acebes, M. A. Del Aguila, Carmen Arias, Armando Agudo, Ruben Saez-Alvarez, Yanira Martín-Acebes, M. A. |
author_facet |
Jiménez De Oya, Nereida Saiz Calahorra, Juan Carlos Martín-Acebes, M. A. Del Aguila, Carmen Arias, Armando Agudo, Ruben Saez-Alvarez, Yanira Martín-Acebes, M. A. |
author_sort |
Jiménez De Oya, Nereida |
title |
Novel Nonnucleoside Inhibitors of Zika Virus Polymerase Identified through the Screening of an Open Library of Antikinetoplastid Compounds |
title_short |
Novel Nonnucleoside Inhibitors of Zika Virus Polymerase Identified through the Screening of an Open Library of Antikinetoplastid Compounds |
title_full |
Novel Nonnucleoside Inhibitors of Zika Virus Polymerase Identified through the Screening of an Open Library of Antikinetoplastid Compounds |
title_fullStr |
Novel Nonnucleoside Inhibitors of Zika Virus Polymerase Identified through the Screening of an Open Library of Antikinetoplastid Compounds |
title_full_unstemmed |
Novel Nonnucleoside Inhibitors of Zika Virus Polymerase Identified through the Screening of an Open Library of Antikinetoplastid Compounds |
title_sort |
novel nonnucleoside inhibitors of zika virus polymerase identified through the screening of an open library of antikinetoplastid compounds |
publisher |
American Society for Microbiology |
publishDate |
2021-08-17 |
url |
http://hdl.handle.net/20.500.12792/6157 http://hdl.handle.net/10261/289827 |
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