Targeting the SARS-CoV-2 RNA Genome with Small Molecule Binders and Ribonuclease Targeting Chimera (RIBOTAC) Degraders
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High Resolution Image Download MS PowerPoint Slide COVID-19 is a global pandemic, thus requiring multiple strategies to develop modalities against it. Herein, we designed multiple bioactive small molecules that target a functional structure within the SARS-CoV-2’s RNA genome, the causative agent of COVID-19. An analysis to characterize the structure of the RNA genome provided a revised model of the SARS-CoV-2 frameshifting element, in particular its attenuator hairpin. By studying an RNA-focused small molecule collection, we identified a drug-like small molecule ( C5 ) that avidly binds to the revised attenuator hairpin structure with a K d of 11 nM. The compound stabilizes the hairpin’s folded state and impairs frameshifting in cells. The ligand was further elaborated into a ribonuclease targeting chimera (RIBOTAC) to recruit a cellular ribonuclease to destroy the viral genome ( C5-RIBOTAC ) and into a covalent molecule ( C5-Chem-CLIP ) that validated direct target engagement and demonstrated its specificity for the viral RNA, as compared to highly expressed host mRNAs. The RIBOTAC lead optimization strategy improved the bioactivity of the compound at least 10-fold. Collectively, these studies demonstrate that the SARS-CoV-2 RNA genome should be considered druggable.
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Incorporation of RNA-binding small molecules into a heterobifunctional design has afforded RIBOTACs that induce proximity between an RNA of interest and a ribonuclease to prompt RNA degradation.
“Moreover, incorporation of RNA-binding small-molecules into a heterobifunctional design has afforded ribonuclease targeting chimeras (RIBOTACs): small molecules that induce proximity between an RNA of interest and a ribonuclease to prompt RNA degradation.37−39”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [38]
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- Authors
- Haniff, H. S., Tong, Y., Liu, X., Chen, J. L., Suresh, B. M., Andrews, R. J., Peterson, J. M., O’Leary, C. A., Benhamou, R. I., Moss, W. N., & Disney, M. D.
- Affiliations
- Scripps Research Institute (US)
- Iowa State University (US)
- Corresponding author
- Disney, Matthew D.
- ORCID
- Venue
- ACS Central Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-09-30
- Volume
- 6
- Issue
- 10
- Pages
- 1713-1721
- ISSN
- 2374-7943 (ISSN-L)
- 2374-7951
- PMC
- PMC7553039
- OpenAlex
- W3091134219
- Cited by
- 205
- References
- 35
- Citations by year
- 2026: 17 · 2025: 29 · 2024: 36 · 2023: 33 · 2022: 44 · 2021: 38 · 2020: 6 · 2014: 1
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- ACS Central Science (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (R01 CA249180)
- National Institute of Neurological Disorders and Stroke (R35 NS116846)
- National Institute of General Medical Sciences (R00GM112877, R01GM133810)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- SARS-CoV-2, COVID-19 pandemic, viral RNA genome, ribosomal frameshifting, covalent inhibitors, target engagement, drug-likeness
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