From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease
The main protease (M<sup>pro</sup>) of the betacoronavirus SARS-CoV-2 is an attractive target for the development of treatments for COVID-19. Structure-based design is a successful approach to discovering new inhibitors of the M<sup>pro</sup>. Starting from crystal structures...
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| Format: | Article |
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MDPI AG
2022-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/13/4292 |
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| author | Matthias Göhl Linlin Zhang Haifa El Kilani Xinyuanyuan Sun Kaixuan Zhang Mark Brönstrup Rolf Hilgenfeld |
| author_facet | Matthias Göhl Linlin Zhang Haifa El Kilani Xinyuanyuan Sun Kaixuan Zhang Mark Brönstrup Rolf Hilgenfeld |
| author_sort | Matthias Göhl |
| collection | DOAJ |
| description | The main protease (M<sup>pro</sup>) of the betacoronavirus SARS-CoV-2 is an attractive target for the development of treatments for COVID-19. Structure-based design is a successful approach to discovering new inhibitors of the M<sup>pro</sup>. Starting from crystal structures of the M<sup>pro</sup> in complexes with the Hepatitis C virus NS3/4A protease inhibitors boceprevir and telaprevir, we optimized the potency of the alpha-ketoamide boceprevir against the M<sup>pro</sup> by replacing its P1 cyclobutyl moiety by a γ-lactam as a glutamine surrogate. The resulting compound, <b>MG-78</b>, exhibited an IC<sub>50</sub> of 13 nM versus the recombinant M<sup>pro</sup>, and similar potency was observed for its P1′ <i>N</i>-methyl derivative <b>MG-131</b>. Crystal structures confirmed the validity of our design concept. In addition to SARS-CoV-2 M<sup>pro</sup> inhibition, we also explored the activity of <b>MG-78</b> against the M<sup>pro</sup> of the alphacoronavirus HCoV NL63 and against enterovirus 3C proteases. The activities were good (0.33 µM, HCoV-NL63 M<sup>pro</sup>), moderate (1.45 µM, Coxsackievirus 3C<sup>pro</sup>), and relatively poor (6.7 µM, enterovirus A71 3C<sup>pro</sup>), respectively. The structural basis for the differences in activities was revealed by X-ray crystallo-graphy. We conclude that the modified boceprevir scaffold is suitable for obtaining high-potency inhibitors of the coronavirus M<sup>pro</sup>s but further optimization would be needed to target enterovirus 3C<sup>pro</sup>s efficiently. |
| first_indexed | 2024-03-09T04:00:17Z |
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| id | doaj.art-488aaa69ec3940b1a6c55eaca08c0fae |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T04:00:17Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-488aaa69ec3940b1a6c55eaca08c0fae2023-12-03T14:14:17ZengMDPI AGMolecules1420-30492022-07-012713429210.3390/molecules27134292From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main ProteaseMatthias Göhl0Linlin Zhang1Haifa El Kilani2Xinyuanyuan Sun3Kaixuan Zhang4Mark Brönstrup5Rolf Hilgenfeld6Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, GermanyInstitute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, GermanyInstitute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, GermanyInstitute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, GermanyInstitute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, GermanyDepartment of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, GermanyInstitute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, GermanyThe main protease (M<sup>pro</sup>) of the betacoronavirus SARS-CoV-2 is an attractive target for the development of treatments for COVID-19. Structure-based design is a successful approach to discovering new inhibitors of the M<sup>pro</sup>. Starting from crystal structures of the M<sup>pro</sup> in complexes with the Hepatitis C virus NS3/4A protease inhibitors boceprevir and telaprevir, we optimized the potency of the alpha-ketoamide boceprevir against the M<sup>pro</sup> by replacing its P1 cyclobutyl moiety by a γ-lactam as a glutamine surrogate. The resulting compound, <b>MG-78</b>, exhibited an IC<sub>50</sub> of 13 nM versus the recombinant M<sup>pro</sup>, and similar potency was observed for its P1′ <i>N</i>-methyl derivative <b>MG-131</b>. Crystal structures confirmed the validity of our design concept. In addition to SARS-CoV-2 M<sup>pro</sup> inhibition, we also explored the activity of <b>MG-78</b> against the M<sup>pro</sup> of the alphacoronavirus HCoV NL63 and against enterovirus 3C proteases. The activities were good (0.33 µM, HCoV-NL63 M<sup>pro</sup>), moderate (1.45 µM, Coxsackievirus 3C<sup>pro</sup>), and relatively poor (6.7 µM, enterovirus A71 3C<sup>pro</sup>), respectively. The structural basis for the differences in activities was revealed by X-ray crystallo-graphy. We conclude that the modified boceprevir scaffold is suitable for obtaining high-potency inhibitors of the coronavirus M<sup>pro</sup>s but further optimization would be needed to target enterovirus 3C<sup>pro</sup>s efficiently.https://www.mdpi.com/1420-3049/27/13/4292SARS-CoV-2COVID-19main protease3C-like proteaseenterovirus 3C proteaseCoxsackievirus B3 |
| spellingShingle | Matthias Göhl Linlin Zhang Haifa El Kilani Xinyuanyuan Sun Kaixuan Zhang Mark Brönstrup Rolf Hilgenfeld From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease Molecules SARS-CoV-2 COVID-19 main protease 3C-like protease enterovirus 3C protease Coxsackievirus B3 |
| title | From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease |
| title_full | From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease |
| title_fullStr | From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease |
| title_full_unstemmed | From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease |
| title_short | From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease |
| title_sort | from repurposing to redesign optimization of boceprevir to highly potent inhibitors of the sars cov 2 main protease |
| topic | SARS-CoV-2 COVID-19 main protease 3C-like protease enterovirus 3C protease Coxsackievirus B3 |
| url | https://www.mdpi.com/1420-3049/27/13/4292 |
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