Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors
The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is amo...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
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| Series: | Pathogens |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-0817/12/2/324 |
| _version_ | 1827756095032000512 |
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| author | Marion Schuller Tryfon Zarganes-Tzitzikas James Bennett Stephane De Cesco Daren Fearon Frank von Delft Oleg Fedorov Paul E. Brennan Ivan Ahel |
| author_facet | Marion Schuller Tryfon Zarganes-Tzitzikas James Bennett Stephane De Cesco Daren Fearon Frank von Delft Oleg Fedorov Paul E. Brennan Ivan Ahel |
| author_sort | Marion Schuller |
| collection | DOAJ |
| description | The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibiotic compound aztreonam, to the active site of the macrodomain provide valuable structure–activity relationship information that support current approaches and open up new avenues for NSP3 macrodomain inhibitor development. |
| first_indexed | 2024-03-11T08:18:21Z |
| format | Article |
| id | doaj.art-d095de8ed820404392759fd4296b33f6 |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-11T08:18:21Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-d095de8ed820404392759fd4296b33f62023-11-16T22:35:03ZengMDPI AGPathogens2076-08172023-02-0112232410.3390/pathogens12020324Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain InhibitorsMarion Schuller0Tryfon Zarganes-Tzitzikas1James Bennett2Stephane De Cesco3Daren Fearon4Frank von Delft5Oleg Fedorov6Paul E. Brennan7Ivan Ahel8Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UKCentre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UKCentre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UKCentre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UKDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UKCentre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UKCentre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UKCentre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UKSir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UKThe worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibiotic compound aztreonam, to the active site of the macrodomain provide valuable structure–activity relationship information that support current approaches and open up new avenues for NSP3 macrodomain inhibitor development.https://www.mdpi.com/2076-0817/12/2/324ADP-ribosylationmacrodomainSARS-CoV-2COVID-19non-structural protein 3 (NSP3)drug discovery and development |
| spellingShingle | Marion Schuller Tryfon Zarganes-Tzitzikas James Bennett Stephane De Cesco Daren Fearon Frank von Delft Oleg Fedorov Paul E. Brennan Ivan Ahel Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors Pathogens ADP-ribosylation macrodomain SARS-CoV-2 COVID-19 non-structural protein 3 (NSP3) drug discovery and development |
| title | Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors |
| title_full | Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors |
| title_fullStr | Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors |
| title_full_unstemmed | Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors |
| title_short | Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors |
| title_sort | discovery and development strategies for sars cov 2 nsp3 macrodomain inhibitors |
| topic | ADP-ribosylation macrodomain SARS-CoV-2 COVID-19 non-structural protein 3 (NSP3) drug discovery and development |
| url | https://www.mdpi.com/2076-0817/12/2/324 |
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