Open AccessTargeting the SARS-CoV-2 RNA Genome with Small Molecule Binders and Ribonuclease Targeting Chimera (RIBOTAC) Degraders
Author(s) -
Hafeez S. Haniff,
Yuquan Tong,
Xiaohui Liu,
Jonathan L. Chen,
Blessy M Suresh,
Ryan J. Andrews,
Jake M. Peterson,
Collin A. O’Leary,
Raphael I. Benhamou,
Walter N. Moss,
Matthew D. Disney
Publication year - 2020
Publication title -
acs central science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.893
H-Index - 76
eISSN - 2374-7951
pISSN - 2374-7943
DOI - 10.1021/acscentsci.0c00984
Subject(s) - rna , ribonuclease , druggability , small molecule , computational biology , genome , chimera (genetics) , biology , ribonuclease iii , riboswitch , polyadenylation , chemistry , genetics , microbiology and biotechnology , non coding rna , rna interference , gene
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.