Comparison of small molecules and oligonucleotides that target a toxic, non-coding RNA.
Potential RNA targets for chemical probes and therapeutic modalities are pervasive in the transcriptome. Oligonucleotide-based therapeutics are commonly used to target RNA sequence. Small molecules are emerging as a modality to target RNA structures selectively, but their development is still in its infancy. In this work, we compare the activity of oligonucleotides and several classes of small molecules that target the non-coding r(CCUG) repeat expansion (r(CCUG)(exp)) that causes myotonic dystrophy type 2 (DM2), an incurable disease that is the second-most common cause of adult onset muscular dystrophy. Small molecule types investigated include monomers, dimers, and multivalent compounds synthesized on-site by using RNA-templated click chemistry. Oligonucleotides investigated include phosphorothioates that cleave their target and vivo-morpholinos that modulate target RNA activity via binding. We show that compounds assembled on-site that recognize structure have the highest potencies amongst small molecules and are similar in potency to a vivo-morpholino modified oligonucleotide that targets sequence. These studies are likely to impact the design of therapeutic modalities targeting other repeats expansions that cause fragile X syndrome and amyotrophic lateral sclerosis, for example.
Departments of Chemistry & Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States.
Matthew G
MG
Costales
Departments of Chemistry & Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States.
Suzanne G
SG
Rzuczek
Departments of Chemistry & Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States. Electronic address: disney@scripps.edu.
Matthew D
MD
Disney
D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D022661:RNA, Untranslated / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D009841:Oligonucleotides; D022661:RNA, Untranslated; D054852:Small Molecule Libraries
Myotonic dystrophy; Oligonucleotides; RNA; Small molecules