Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules.

Published version
Repository DOI

Type
Article
Change log
Authors
Mikutis, Sigitas 
Rebelo, Maria 
Yankova, Eliza 
Gu, Muxin 
Tang, Cong 
Abstract

Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleotides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases.

Description
Keywords
3404 Medicinal and Biomolecular Chemistry, 34 Chemical Sciences, Prevention, Orphan Drug, Biodefense, Genetics, Emerging Infectious Diseases, Vaccine Related, Rare Diseases, 5.1 Pharmaceuticals, 5 Development of treatments and therapeutic interventions, 3 Good Health and Well Being
Journal Title
ACS Cent Sci
Conference Name
Journal ISSN
2374-7943
2374-7951
Volume Title
9
Publisher
American Chemical Society (ACS)
Sponsorship
Cancer Research UK (23015)