Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors
The COVID-19 pandemic continues unabated, emphasizing the need for additional antiviral treatment options to prevent hospitalization and death of patients infected with SARS-CoV-2. The papain-like protease (PLpro) domain is part of the SARS-CoV-2 non-structural protein (nsp)-3, and represents an ess...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2022.861209/full |
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| author | Dale J. Calleja Nathan Kuchel Bernadine G. C. Lu Richard W. Birkinshaw Theresa Klemm Marcel Doerflinger James P. Cooney Liana Mackiewicz Amanda E. Au Yu Q. Yap Timothy R Blackmore Kasiram Katneni Elly Crighton Janet Newman Kate E. Jarman Melissa J. Call Bernhard C. Lechtenberg Peter E. Czabotar Marc Pellegrini Susan A. Charman Kym N. Lowes Jeffrey P. Mitchell Ueli Nachbur Guillaume Lessene Guillaume Lessene David Komander |
| author_facet | Dale J. Calleja Nathan Kuchel Bernadine G. C. Lu Richard W. Birkinshaw Theresa Klemm Marcel Doerflinger James P. Cooney Liana Mackiewicz Amanda E. Au Yu Q. Yap Timothy R Blackmore Kasiram Katneni Elly Crighton Janet Newman Kate E. Jarman Melissa J. Call Bernhard C. Lechtenberg Peter E. Czabotar Marc Pellegrini Susan A. Charman Kym N. Lowes Jeffrey P. Mitchell Ueli Nachbur Guillaume Lessene Guillaume Lessene David Komander |
| author_sort | Dale J. Calleja |
| collection | DOAJ |
| description | The COVID-19 pandemic continues unabated, emphasizing the need for additional antiviral treatment options to prevent hospitalization and death of patients infected with SARS-CoV-2. The papain-like protease (PLpro) domain is part of the SARS-CoV-2 non-structural protein (nsp)-3, and represents an essential protease and validated drug target for preventing viral replication. PLpro moonlights as a deubiquitinating (DUB) and deISGylating enzyme, enabling adaptation of a DUB high throughput (HTS) screen to identify PLpro inhibitors. Drug repurposing has been a major focus through the COVID-19 pandemic as it may provide a fast and efficient route for identifying clinic-ready, safe-in-human antivirals. We here report our effort to identify PLpro inhibitors by screening the ReFRAME library of 11,804 compounds, showing that none inhibit PLpro with any reasonable activity or specificity to justify further progression towards the clinic. We also report our latest efforts to improve piperidine-scaffold inhibitors, 5c and 3k, originally developed for SARS-CoV PLpro. We report molecular details of binding and selectivity, as well as in vitro absorption, distribution, metabolism and excretion (ADME) studies of this scaffold. A co-crystal structure of SARS-CoV-2 PLpro bound to inhibitor 3k guides medicinal chemistry efforts to improve binding and ADME characteristics. We arrive at compounds with improved and favorable solubility and stability characteristics that are tested for inhibiting viral replication. Whilst still requiring significant improvement, our optimized small molecule inhibitors of PLpro display decent antiviral activity in an in vitro SARS-CoV-2 infection model, justifying further optimization. |
| first_indexed | 2024-04-12T22:22:58Z |
| format | Article |
| id | doaj.art-78066ca793204c13adcbf61221072dfc |
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| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-04-12T22:22:58Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Chemistry |
| spelling | doaj.art-78066ca793204c13adcbf61221072dfc2022-12-22T03:14:18ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462022-04-011010.3389/fchem.2022.861209861209Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro InhibitorsDale J. Calleja0Nathan Kuchel1Bernadine G. C. Lu2Richard W. Birkinshaw3Theresa Klemm4Marcel Doerflinger5James P. Cooney6Liana Mackiewicz7Amanda E. Au8Yu Q. Yap9Timothy R Blackmore10Kasiram Katneni11Elly Crighton12Janet Newman13Kate E. Jarman14Melissa J. Call15Bernhard C. Lechtenberg16Peter E. Czabotar17Marc Pellegrini18Susan A. Charman19Kym N. Lowes20Jeffrey P. Mitchell21Ueli Nachbur22Guillaume Lessene23Guillaume Lessene24David Komander25Department of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, AustraliaCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, AustraliaCommonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program, Parkville, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC, AustraliaDepartment of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, AustraliaThe COVID-19 pandemic continues unabated, emphasizing the need for additional antiviral treatment options to prevent hospitalization and death of patients infected with SARS-CoV-2. The papain-like protease (PLpro) domain is part of the SARS-CoV-2 non-structural protein (nsp)-3, and represents an essential protease and validated drug target for preventing viral replication. PLpro moonlights as a deubiquitinating (DUB) and deISGylating enzyme, enabling adaptation of a DUB high throughput (HTS) screen to identify PLpro inhibitors. Drug repurposing has been a major focus through the COVID-19 pandemic as it may provide a fast and efficient route for identifying clinic-ready, safe-in-human antivirals. We here report our effort to identify PLpro inhibitors by screening the ReFRAME library of 11,804 compounds, showing that none inhibit PLpro with any reasonable activity or specificity to justify further progression towards the clinic. We also report our latest efforts to improve piperidine-scaffold inhibitors, 5c and 3k, originally developed for SARS-CoV PLpro. We report molecular details of binding and selectivity, as well as in vitro absorption, distribution, metabolism and excretion (ADME) studies of this scaffold. A co-crystal structure of SARS-CoV-2 PLpro bound to inhibitor 3k guides medicinal chemistry efforts to improve binding and ADME characteristics. We arrive at compounds with improved and favorable solubility and stability characteristics that are tested for inhibiting viral replication. Whilst still requiring significant improvement, our optimized small molecule inhibitors of PLpro display decent antiviral activity in an in vitro SARS-CoV-2 infection model, justifying further optimization.https://www.frontiersin.org/articles/10.3389/fchem.2022.861209/fullNsp3PLproinhibitorSARS-CoV-2repurposingstructure |
| spellingShingle | Dale J. Calleja Nathan Kuchel Bernadine G. C. Lu Richard W. Birkinshaw Theresa Klemm Marcel Doerflinger James P. Cooney Liana Mackiewicz Amanda E. Au Yu Q. Yap Timothy R Blackmore Kasiram Katneni Elly Crighton Janet Newman Kate E. Jarman Melissa J. Call Bernhard C. Lechtenberg Peter E. Czabotar Marc Pellegrini Susan A. Charman Kym N. Lowes Jeffrey P. Mitchell Ueli Nachbur Guillaume Lessene Guillaume Lessene David Komander Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors Frontiers in Chemistry Nsp3 PLpro inhibitor SARS-CoV-2 repurposing structure |
| title | Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors |
| title_full | Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors |
| title_fullStr | Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors |
| title_full_unstemmed | Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors |
| title_short | Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors |
| title_sort | insights into drug repurposing as well as specificity and compound properties of piperidine based sars cov 2 plpro inhibitors |
| topic | Nsp3 PLpro inhibitor SARS-CoV-2 repurposing structure |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2022.861209/full |
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