A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo
Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting annually in ~219,000 deaths and a societal cost of ~USD 60 billion, and no antivirals or vaccines are available. Here, we assess the anti-norovirus activity of new peptidomimetic aldehydes related to the protease...
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MDPI AG
2021-09-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/13/9/1852 |
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| author | Jana Van Dycke Wenhao Dai Zoe Stylianidou Jian Li Arno Cuvry Emma Roux Bingqian Li Jasper Rymenants Lindsey Bervoets Peter de Witte Hong Liu Johan Neyts Joana Rocha-Pereira |
| author_facet | Jana Van Dycke Wenhao Dai Zoe Stylianidou Jian Li Arno Cuvry Emma Roux Bingqian Li Jasper Rymenants Lindsey Bervoets Peter de Witte Hong Liu Johan Neyts Joana Rocha-Pereira |
| author_sort | Jana Van Dycke |
| collection | DOAJ |
| description | Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting annually in ~219,000 deaths and a societal cost of ~USD 60 billion, and no antivirals or vaccines are available. Here, we assess the anti-norovirus activity of new peptidomimetic aldehydes related to the protease inhibitor rupintrivir. The early hit compound <b>4</b> inhibited the replication of murine norovirus (MNV) and the HuNoV GI.1 replicon in vitro (EC<sub>50</sub> ~1 µM) and swiftly cleared the HuNoV GI.1 replicon from the cells. Compound <b>4</b> still inhibits the proteolytic activity. We selected a resistant GI.1 replicon, with a mutation (I109V) in a highly conserved region of the viral protease, conferring a low yield of resistance against compound <b>4</b> and rupintrivir. After testing new derivatives, compound <b>10d</b> was the most potent (EC<sub>50</sub> nanomolar range). Molecular docking indicated that the aldehyde group of compounds <b>4</b> and <b>10d</b> bind with Cys139 in the HuNoV 3CL protease by a covalent linkage. Finally, compound <b>10d</b> inhibited the replication of HuNoV GII.4 in infected zebrafish larvae, and PK studies in mice showed an adequate profile. |
| first_indexed | 2024-03-10T07:07:54Z |
| format | Article |
| id | doaj.art-a4ae9d5cb59a4e8db1379b4b9612adf8 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T07:07:54Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-a4ae9d5cb59a4e8db1379b4b9612adf82023-11-22T15:38:56ZengMDPI AGViruses1999-49152021-09-01139185210.3390/v13091852A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In VivoJana Van Dycke0Wenhao Dai1Zoe Stylianidou2Jian Li3Arno Cuvry4Emma Roux5Bingqian Li6Jasper Rymenants7Lindsey Bervoets8Peter de Witte9Hong Liu10Johan Neyts11Joana Rocha-Pereira12Laboratory of Virology and Chemotherapy, KU Leuven–Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000 Leuven, BelgiumState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, ChinaLaboratory of Virology and Chemotherapy, KU Leuven–Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000 Leuven, BelgiumState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, ChinaLaboratory of Virology and Chemotherapy, KU Leuven–Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000 Leuven, BelgiumLaboratory of Virology and Chemotherapy, KU Leuven–Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000 Leuven, BelgiumState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, ChinaLaboratory of Virology and Chemotherapy, KU Leuven–Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000 Leuven, BelgiumLaboratory of Virology and Chemotherapy, KU Leuven–Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000 Leuven, BelgiumLaboratory for Molecular Biodiscovery, KU Leuven–Department of Pharmaceutical and Pharmacological Sciences, 3000 Leuven, BelgiumState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, ChinaLaboratory of Virology and Chemotherapy, KU Leuven–Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000 Leuven, BelgiumLaboratory of Virology and Chemotherapy, KU Leuven–Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000 Leuven, BelgiumHuman noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting annually in ~219,000 deaths and a societal cost of ~USD 60 billion, and no antivirals or vaccines are available. Here, we assess the anti-norovirus activity of new peptidomimetic aldehydes related to the protease inhibitor rupintrivir. The early hit compound <b>4</b> inhibited the replication of murine norovirus (MNV) and the HuNoV GI.1 replicon in vitro (EC<sub>50</sub> ~1 µM) and swiftly cleared the HuNoV GI.1 replicon from the cells. Compound <b>4</b> still inhibits the proteolytic activity. We selected a resistant GI.1 replicon, with a mutation (I109V) in a highly conserved region of the viral protease, conferring a low yield of resistance against compound <b>4</b> and rupintrivir. After testing new derivatives, compound <b>10d</b> was the most potent (EC<sub>50</sub> nanomolar range). Molecular docking indicated that the aldehyde group of compounds <b>4</b> and <b>10d</b> bind with Cys139 in the HuNoV 3CL protease by a covalent linkage. Finally, compound <b>10d</b> inhibited the replication of HuNoV GII.4 in infected zebrafish larvae, and PK studies in mice showed an adequate profile.https://www.mdpi.com/1999-4915/13/9/1852Caliciviridaeantiviralssmall moleculedanio rerioinfection |
| spellingShingle | Jana Van Dycke Wenhao Dai Zoe Stylianidou Jian Li Arno Cuvry Emma Roux Bingqian Li Jasper Rymenants Lindsey Bervoets Peter de Witte Hong Liu Johan Neyts Joana Rocha-Pereira A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo Viruses Caliciviridae antivirals small molecule danio rerio infection |
| title | A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo |
| title_full | A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo |
| title_fullStr | A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo |
| title_full_unstemmed | A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo |
| title_short | A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo |
| title_sort | novel class of norovirus inhibitors targeting the viral protease with potent antiviral activity in vitro and in vivo |
| topic | Caliciviridae antivirals small molecule danio rerio infection |
| url | https://www.mdpi.com/1999-4915/13/9/1852 |
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