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Anti-frameshifting Ligand Reduces the Conformational Plasticity of the SARS Virus Pseudoknot

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    Anti-frameshifting Ligand Reduces the Conformational Plasticity of the SARS Virus Pseudoknot
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    † Department of Physics, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
    ‡ National Institute for Nanotechnology, National Research Council, Edmonton, Alberta T6G 2M9, Canada
    [email protected]
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    Cite this: J. Am. Chem. Soc. 2014, 136, 6, 2196–2199
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    https://doi.org/10.1021/ja410344b
    Published January 21, 2014
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    Abstract

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    Programmed −1 ribosomal frameshifting (−1 PRF) stimulated by mRNA pseudoknots regulates gene expression in many viruses, making pseudoknots potential targets for anti-viral drugs. The mechanism by which pseudoknots trigger −1 PRF, however, remains controversial, with several competing models. Recent work showed that high −1 PRF efficiency was linked to high pseudoknot conformational plasticity via the formation of alternate conformers. We tested whether pseudoknots bound with an anti-frameshifting ligand exhibited a similar correlation between conformational plasticity and −1 PRF efficiency by measuring the effects of a ligand that was found to inhibit −1 PRF in the SARS coronavirus on the conformational dynamics of the SARS pseudoknot. Using single-molecule force spectroscopy to unfold pseudoknots mechanically, we found that the ligand binding effectively abolished the formation of alternate conformers. This result extends the connection between −1 PRF and conformational dynamics and, moreover, suggests that targeting the conformational dynamics of pseudoknots may be an effective strategy for anti-viral drug design.

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    Materials and methods, Eqns S1–S3, and Table S1. This material is available free of charge via the Internet at http://pubs.acs.org.

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    8. Tamar Schlick, Qiyao Zhu, Abhishek Dey, Swati Jain, Shuting Yan, Alain Laederach. To Knot or Not to Knot: Multiple Conformations of the SARS-CoV-2 Frameshifting RNA Element. Journal of the American Chemical Society 2021, 143 (30) , 11404-11422. https://doi.org/10.1021/jacs.1c03003
    9. Javier Bonet‐Aleta, Tomoaki Maehara, Benjamin A. Craig, Gonçalo J. L. Bernardes. Small Molecule RNA Degraders. Angewandte Chemie 2024, 136 (47) https://doi.org/10.1002/ange.202412925
    10. Javier Bonet‐Aleta, Tomoaki Maehara, Benjamin A. Craig, Gonçalo J. L. Bernardes. Small Molecule RNA Degraders. Angewandte Chemie International Edition 2024, 63 (47) https://doi.org/10.1002/anie.202412925
    11. Elinore A. VanGraafeiland, Diego M. Arévalo, Benjamin L. Miller. Approaches to the Identification of Molecules Altering Programmed Ribosomal Frameshifting in Viruses. 2024, 253-279. https://doi.org/10.1002/9783527840458.ch10
    12. Justin Aruda, Scott L. Grote, Silvi Rouskin. Untangling the pseudoknots of SARS-CoV-2: Insights into structural heterogeneity and plasticity. Current Opinion in Structural Biology 2024, 88 , 102912. https://doi.org/10.1016/j.sbi.2024.102912
    13. Yuanzhe Zhou, Shi-Jie Chen. Advances in machine-learning approaches to RNA-targeted drug design. Artificial Intelligence Chemistry 2024, 2 (1) , 100053. https://doi.org/10.1016/j.aichem.2024.100053
    14. Luke Trinity, Ulrike Stege, Hosna Jabbari, . Tying the knot: Unraveling the intricacies of the coronavirus frameshift pseudoknot. PLOS Computational Biology 2024, 20 (5) , e1011787. https://doi.org/10.1371/journal.pcbi.1011787
    15. Kodai Machida, Rin Tanaka, Seraya Miki, Shotaro Noseda, Mayumi Yuasa-Sunagawa, Hiroaki Imataka. High-Throughput Screening for a SARS-CoV-2 Frameshifting Inhibitor Using a Cell-Free Protein Synthesis System. BioTechniques 2024, 76 (4) , 161-168. https://doi.org/10.2144/btn-2023-0102
    16. Chris H. Hill, Ian Brierley. Structural and Functional Insights into Viral Programmed Ribosomal Frameshifting. Annual Review of Virology 2023, 10 (1) , 217-242. https://doi.org/10.1146/annurev-virology-111821-120646
    17. Gregory Mathez, Valeria Cagno. Small Molecules Targeting Viral RNA. International Journal of Molecular Sciences 2023, 24 (17) , 13500. https://doi.org/10.3390/ijms241713500
    18. Panagiotis Poulis, Frank Peske, Marina V. Rodnina. The many faces of ribosome translocation along the mRNA: reading frame maintenance, ribosome frameshifting and translational bypassing. Biological Chemistry 2023, 404 (8-9) , 755-767. https://doi.org/10.1515/hsz-2023-0142
    19. Thomas Kenderdine, Dan Fabris. The multifaceted roles of mass spectrometric analysis in nucleic acids drug discovery and development. Mass Spectrometry Reviews 2023, 42 (4) , 1332-1357. https://doi.org/10.1002/mas.21766
    20. Luke Trinity, Ian Wark, Lance Lansing, Hosna Jabbari, Ulrike Stege, . Shapify: Paths to SARS-CoV-2 frameshifting pseudoknot. PLOS Computational Biology 2023, 19 (2) , e1010922. https://doi.org/10.1371/journal.pcbi.1010922
    21. Tamar Schlick, Shuting Yan. Modeling and Simulating RNA: Combining Structural, Dynamic, and Evolutionary Perspectives for Coronavirus Applications. 2023, 886-894. https://doi.org/10.1016/B978-0-12-821978-2.00118-5
    22. Matthew T.J. Halma, Jack A. Tuszynski, Gijs J.L. Wuite. Optical tweezers for drug discovery. Drug Discovery Today 2023, 28 (1) , 103443. https://doi.org/10.1016/j.drudis.2022.103443
    23. Shuting Yan, Qiyao Zhu, Swati Jain, Tamar Schlick. Length-dependent motions of SARS-CoV-2 frameshifting RNA pseudoknot and alternative conformations suggest avenues for frameshifting suppression. Nature Communications 2022, 13 (1) https://doi.org/10.1038/s41467-022-31353-w
    24. Maclean Bassett, Marco Salemi, Brittany Rife Magalis. Lessons Learned and Yet-to-Be Learned on the Importance of RNA Structure in SARS-CoV-2 Replication. Microbiology and Molecular Biology Reviews 2022, 86 (3) https://doi.org/10.1128/mmbr.00057-21
    25. Stefan Buck, Lukas Pekarek, Neva Caliskan. POTATO: Automated pipeline for batch analysis of optical tweezers data. Biophysical Journal 2022, 121 (15) , 2830-2839. https://doi.org/10.1016/j.bpj.2022.06.030
    26. Martina Zafferani, Dhanasheel Muralidharan, Nadeska I. Montalvan, Amanda E. Hargrove. RT-qPCR as a screening platform for mutational and small molecule impacts on structural stability of RNA tertiary structures. RSC Chemical Biology 2022, 3 (7) , 905-915. https://doi.org/10.1039/D2CB00015F
    27. Ke Tang, Jorjethe Roca, Rong Chen, Anjum Ansari, Jie Liang. Thermodynamics of unfolding mechanisms of mouse mammary tumor virus pseudoknot from a coarse-grained loop-entropy model. Journal of Biological Physics 2022, 48 (2) , 129-150. https://doi.org/10.1007/s10867-022-09602-2
    28. Yuanzhe Zhou, Yangwei Jiang, Shi‐Jie Chen. RNA –ligand molecular docking: Advances and challenges. WIREs Computational Molecular Science 2022, 12 (3) https://doi.org/10.1002/wcms.1571
    29. Sneha Munshi, Krishna Neupane, Sandaru M. Ileperuma, Matthew T. J. Halma, Jamie A. Kelly, Clarissa F. Halpern, Jonathan D. Dinman, Sarah Loerch, Michael T. Woodside. Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses. Viruses 2022, 14 (2) , 177. https://doi.org/10.3390/v14020177
    30. Zhiguo Wang, Baofeng Yang. Polypharmacology in Drug Design and Discovery—Basis for Rational Design of Multitarget Drugs. 2022, 397-533. https://doi.org/10.1007/978-3-031-04998-9_12
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    39. Tamar Schlick, Qiyao Zhu, Swati Jain, Shuting Yan. Structure-altering mutations of the SARS-CoV-2 frameshifting RNA element. Biophysical Journal 2021, 120 (6) , 1040-1053. https://doi.org/10.1016/j.bpj.2020.10.012
    40. Jamie A. Kelly, Michael T. Woodside, Jonathan D. Dinman. Programmed −1 Ribosomal Frameshifting in coronaviruses: A therapeutic target. Virology 2021, 554 , 75-82. https://doi.org/10.1016/j.virol.2020.12.010
    41. Sara Ibrahim Omar, Meng Zhao, Rohith Vedhthaanth Sekar, Sahar Arbabi Moghadam, Jack A. Tuszynski, Michael T. Woodside, . Modeling the structure of the frameshift-stimulatory pseudoknot in SARS-CoV-2 reveals multiple possible conformers. PLOS Computational Biology 2021, 17 (1) , e1008603. https://doi.org/10.1371/journal.pcbi.1008603
    42. Kai-Chun Chang, Jin-Der Wen. Programmed −1 ribosomal frameshifting from the perspective of the conformational dynamics of mRNA and ribosomes. Computational and Structural Biotechnology Journal 2021, 19 , 3580-3588. https://doi.org/10.1016/j.csbj.2021.06.015
    43. Matthew T. J. Halma, Dustin B. Ritchie, Michael T. Woodside. Conformational Shannon Entropy of mRNA Structures from Force Spectroscopy Measurements Predicts the Efficiency of − 1 Programmed Ribosomal Frameshift Stimulation. Physical Review Letters 2021, 126 (3) https://doi.org/10.1103/PhysRevLett.126.038102
    44. Krishna Neupane, Sneha Munshi, Meng Zhao, Dustin B. Ritchie, Sandaru M. Ileperuma, Michael T. Woodside. Anti-Frameshifting Ligand Active against SARS Coronavirus-2 Is Resistant to Natural Mutations of the Frameshift-Stimulatory Pseudoknot. Journal of Molecular Biology 2020, 432 (21) , 5843-5847. https://doi.org/10.1016/j.jmb.2020.09.006
    45. Ai-Ming Yu, Young Hee Choi, Mei-Juan Tu. RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges. Pharmacological Reviews 2020, 72 (4) , 862-898. https://doi.org/10.1124/pr.120.019554
    46. Jamie A. Kelly, Alexandra N. Olson, Krishna Neupane, Sneha Munshi, Josue San Emeterio, Lois Pollack, Michael T. Woodside, Jonathan D. Dinman. Structural and functional conservation of the programmed −1 ribosomal frameshift signal of SARS coronavirus 2 (SARS-CoV-2). Journal of Biological Chemistry 2020, 295 (31) , 10741-10748. https://doi.org/10.1074/jbc.AC120.013449
    47. Matthew T. J. Halma, Dustin B. Ritchie, Tonia R. Cappellano, Krishna Neupane, Michael T. Woodside. Complex dynamics under tension in a high-efficiency frameshift stimulatory structure. Proceedings of the National Academy of Sciences 2019, 116 (39) , 19500-19505. https://doi.org/10.1073/pnas.1905258116
    48. A. Di Giorgio, M. Duca. Synthetic small-molecule RNA ligands: future prospects as therapeutic agents. MedChemComm 2019, 10 (8) , 1242-1255. https://doi.org/10.1039/C9MD00195F
    49. Bo Wu, Haibo Zhang, Ruirui Sun, Sijia Peng, Barry S Cooperman, Yale E Goldman, Chunlai Chen. Translocation kinetics and structural dynamics of ribosomes are modulated by the conformational plasticity of downstream pseudoknots. Nucleic Acids Research 2018, 46 (18) , 9736-9748. https://doi.org/10.1093/nar/gky636
    50. Katherine Deigan Warner, Christine E. Hajdin, Kevin M. Weeks. Principles for targeting RNA with drug-like small molecules. Nature Reviews Drug Discovery 2018, 17 (8) , 547-558. https://doi.org/10.1038/nrd.2018.93
    51. Thomas E. Dever, Jonathan D. Dinman, Rachel Green. Translation Elongation and Recoding in Eukaryotes. Cold Spring Harbor Perspectives in Biology 2018, 10 (8) , a032649. https://doi.org/10.1101/cshperspect.a032649
    52. Dustin B. Ritchie, Tonia R. Cappellano, Collin Tittle, Negar Rezajooei, Logan Rouleau, William K.A. Sikkema, Michael T. Woodside. Conformational dynamics of the frameshift stimulatory structure in HIV-1. RNA 2017, 23 (9) , 1376-1384. https://doi.org/10.1261/rna.061655.117
    53. Yu-Ting Chen, Kai-Chun Chang, Hao-Teng Hu, Yi-Lan Chen, You-Hsin Lin, Chiung-Fang Hsu, Cheng-Fu Chang, Kung-Yao Chang, Jin-Der Wen. Coordination among tertiary base pairs results in an efficient frameshift-stimulating RNA pseudoknot. Nucleic Acids Research 2017, 45 (10) , 6011-6022. https://doi.org/10.1093/nar/gkx134
    54. Thomas Hermann. Viral RNA Targets and Their Small Molecule Ligands. 2017, 111-134. https://doi.org/10.1007/7355_2016_20
    55. Thomas Hermann. Small molecules targeting viral RNA. WIREs RNA 2016, 7 (6) , 726-743. https://doi.org/10.1002/wrna.1373
    56. Eric Jan, Ian Mohr, Derek Walsh. A Cap-to-Tail Guide to mRNA Translation Strategies in Virus-Infected Cells. Annual Review of Virology 2016, 3 (1) , 283-307. https://doi.org/10.1146/annurev-virology-100114-055014
    57. Colleen M. Connelly, Michelle H. Moon, John S. Schneekloth. The Emerging Role of RNA as a Therapeutic Target for Small Molecules. Cell Chemical Biology 2016, 23 (9) , 1077-1090. https://doi.org/10.1016/j.chembiol.2016.05.021
    58. Koen Visscher. −1 Programmed Ribosomal Frameshifting as a Force-Dependent Process. 2016, 45-72. https://doi.org/10.1016/bs.pmbts.2015.11.003
    59. Dustin B Ritchie, Michael T Woodside. Probing the structural dynamics of proteins and nucleic acids with optical tweezers. Current Opinion in Structural Biology 2015, 34 , 43-51. https://doi.org/10.1016/j.sbi.2015.06.006
    60. Megan C. Engel, Dustin B. Ritchie, Daniel A. N. Foster, Kevin S. D. Beach, Michael T. Woodside. Reconstructing Folding Energy Landscape Profiles from Nonequilibrium Pulling Curves with an Inverse Weierstrass Integral Transform. Physical Review Letters 2014, 113 (23) https://doi.org/10.1103/PhysRevLett.113.238104
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    Cite this: J. Am. Chem. Soc. 2014, 136, 6, 2196–2199
    Click to copy citationCitation copied!
    https://doi.org/10.1021/ja410344b
    Published January 21, 2014
    Copyright © 2014 American Chemical Society
    Request reuse permissions

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