Targeting the SARS-CoV‑2 RNA genome with small molecule binders and ribonuclease targeting chimera (RIBOTAC) degraders

September 30, 2020

Haniff, H., Tong, Y., Liu, X., et al.

ACS Central Science 2020, vol: 6(10) doi: 10.1021/acscentsci.0c00984


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 Kd 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.

View Publication

Topics: PROTACs, Monolith – MicroScale Thermophoresis, MST,  Publications




Previous Article
A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer
A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer

Up next
When binding affinity matters.
When binding affinity matters.

Have a question about Monolith?

Contact Specialist

Sign up to receive
the latest NanoTemper news, product updates, event announcements and more

First Name
Last Name
Company Name
Agree to Subscribe & Privacy Policy*
*I have fully read, understood and agree to the Privacy Policy. I accept the storing and processing of my personal data by NanoTemper as described in the Privacy Policy.

By completing this form, you provide us consent to contact you with educational content, news and information about our products, services and events. You may unsubscribe at any time.
Thank you!
Error - something went wrong!