Small-molecule screening of ribonuclease L binders for RNA degradation
Small molecules targeting the ubiquitous latent ribonuclease (RNase L), which has limited sequence specificity toward single-stranded RNA substrates, hold great potential to be developed as broad-spectrum antiviral drugs by modulating the RNase L-mediated innate immune responses. The recent developm...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-10-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222009787 |
| _version_ | 1811210421006237696 |
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| author | Lydia Borgelt Neele Haacke Philipp Lampe Xiaqiu Qiu Raphael Gasper Damian Schiller Jimin Hwang Sonja Sievers Peng Wu |
| author_facet | Lydia Borgelt Neele Haacke Philipp Lampe Xiaqiu Qiu Raphael Gasper Damian Schiller Jimin Hwang Sonja Sievers Peng Wu |
| author_sort | Lydia Borgelt |
| collection | DOAJ |
| description | Small molecules targeting the ubiquitous latent ribonuclease (RNase L), which has limited sequence specificity toward single-stranded RNA substrates, hold great potential to be developed as broad-spectrum antiviral drugs by modulating the RNase L-mediated innate immune responses. The recent development of proximity-inducing bifunctional molecules, as described in the strategy of ribonuclease targeting chimeras, demonstrated that small-molecule RNase L activators can function as the essential RNase L-recruiting component to design bifunctional molecules for targeted RNA degradation. However, only a single screening study on small-molecule RNase L activators with poor potency has been reported to date. Herein, we established a FRET assay and conducted a screening of 240,000 small molecules to identify new RNase L activators with improved potency. The extremely low hit rate of less than 0.03% demonstrated the challenging nature of RNase L activation by small molecules available from current screening collections. A few hit compounds induced enhanced thermal stability of RNase L upon binding, although validation assays did not lead to the identification of compounds with significantly improved RNase L activating potency. The sulfonamide compound 17 induced a thermal shift of ~ 0.9 °C upon binding to RNase L, induced significant apoptosis in cancer cells, and showed single-digit micromolar inhibitory activity against cancer cell proliferation. This study paves the way for future structural optimization for the development of small-molecule RNase L binders. |
| first_indexed | 2024-04-12T04:54:12Z |
| format | Article |
| id | doaj.art-fe529423d9a04d80b093494c78f19276 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-12T04:54:12Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-fe529423d9a04d80b093494c78f192762022-12-22T03:47:11ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-10-01154113589Small-molecule screening of ribonuclease L binders for RNA degradationLydia Borgelt0Neele Haacke1Philipp Lampe2Xiaqiu Qiu3Raphael Gasper4Damian Schiller5Jimin Hwang6Sonja Sievers7Peng Wu8Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund 44227, GermanyChemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund 44227, GermanyDepartment of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Compound Management and Screening Center, Dortmund 44227, GermanyChemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund 44227, GermanyCrystallography and Biophysics Unit, Max Planck Institute of Molecular Physiology, Dortmund 44227, GermanyFaculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund 44227, GermanyChemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund 44227, GermanyDepartment of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Compound Management and Screening Center, Dortmund 44227, GermanyChemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany; Corresponding author at: Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund 44227, Germany.Small molecules targeting the ubiquitous latent ribonuclease (RNase L), which has limited sequence specificity toward single-stranded RNA substrates, hold great potential to be developed as broad-spectrum antiviral drugs by modulating the RNase L-mediated innate immune responses. The recent development of proximity-inducing bifunctional molecules, as described in the strategy of ribonuclease targeting chimeras, demonstrated that small-molecule RNase L activators can function as the essential RNase L-recruiting component to design bifunctional molecules for targeted RNA degradation. However, only a single screening study on small-molecule RNase L activators with poor potency has been reported to date. Herein, we established a FRET assay and conducted a screening of 240,000 small molecules to identify new RNase L activators with improved potency. The extremely low hit rate of less than 0.03% demonstrated the challenging nature of RNase L activation by small molecules available from current screening collections. A few hit compounds induced enhanced thermal stability of RNase L upon binding, although validation assays did not lead to the identification of compounds with significantly improved RNase L activating potency. The sulfonamide compound 17 induced a thermal shift of ~ 0.9 °C upon binding to RNase L, induced significant apoptosis in cancer cells, and showed single-digit micromolar inhibitory activity against cancer cell proliferation. This study paves the way for future structural optimization for the development of small-molecule RNase L binders.http://www.sciencedirect.com/science/article/pii/S0753332222009787Small moleculesBindersInnate immune responseRibonucleaseRNA degradation |
| spellingShingle | Lydia Borgelt Neele Haacke Philipp Lampe Xiaqiu Qiu Raphael Gasper Damian Schiller Jimin Hwang Sonja Sievers Peng Wu Small-molecule screening of ribonuclease L binders for RNA degradation Biomedicine & Pharmacotherapy Small molecules Binders Innate immune response Ribonuclease RNA degradation |
| title | Small-molecule screening of ribonuclease L binders for RNA degradation |
| title_full | Small-molecule screening of ribonuclease L binders for RNA degradation |
| title_fullStr | Small-molecule screening of ribonuclease L binders for RNA degradation |
| title_full_unstemmed | Small-molecule screening of ribonuclease L binders for RNA degradation |
| title_short | Small-molecule screening of ribonuclease L binders for RNA degradation |
| title_sort | small molecule screening of ribonuclease l binders for rna degradation |
| topic | Small molecules Binders Innate immune response Ribonuclease RNA degradation |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222009787 |
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