Jonathan Chen

• The Scripps Research Institute

Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is caused by the aberrant alternative pre-mRNA splicing of microtubule-associated protein tau ( MAPT ) exon 10, the inclusion of which encodes for a toxic tau protein harboring four microtube domains (4R tau). Here, we describe the design of an RNA-targeted small molecule t...

RNA repeat expansions fold into stable structures and cause microsatellite diseases such as Huntington’s disease (HD), myotonic dystrophy type 1 (DM1), and spinocerebellar ataxias (SCAs). The trinucleotide expansion of r(CAG), or r(CAG) exp , causes both HD and SCA3, and the RNA’s toxicity has been traced to its translation into polyglutamine (poly...

Trinucleotide repeat expansions fold into long, stable hairpins and cause a variety of incurable RNA gain-of-function diseases such as Huntington’s disease, the myotonic dystrophies, and spinocerebellar ataxias. One approach for treating these diseases is to bind small molecules to the structured RNAs. Both Huntington’s disease-like 2 (HDL2) and my...

Due to the importance of 4R tau in the pathogenicity of primary tauopathies, it has been challenging to model these diseases in iPSC-derived neurons, which express very low levels of 4R tau. To address this problem we have developed a panel of isogenic iPSC lines carrying the MAPT splice-site mutations S305S, S305I or S305N, derived from four diffe...

Genetically defined amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), collectively named c9ALS/FTD, are triggered by hexanucleotide GGGGCC repeat expansions [r(G4C2)exp] within the C9orf72 gene. In these diseases, neuronal loss occurs through an interplay of deleterious phenotypes, including r(G4C2)exp RNA gain-of-function mech...

Many diseases are caused by toxic RNA repeats. Herein, we designed a lead small molecule that binds the structure of the r(CUG) repeat expansion [r(CUG) exp] that causes myotonic dystrophy type 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD) and rescues disease biology in patient-derived cells and in vivo. Interestingly, the compound's downs...

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...

RNA molecules have a variety of cellular functions that can drive disease pathologies. They are without a doubt one of the most intriguing yet controversial small-molecule drug targets. The ability to widely target RNA with small molecules could be revolutionary, once the right tools, assays, and targets are selected, thereby defining which biomole...

We describe the design of a small molecule that binds the structure of a r(CUG) repeat expansion [r(CUG) exp ] and reverses molecular defects in two diseases mediated by the RNA - myotonic dystrophy type 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD). Thus, a single structure-specific ligand has potential therapeutic benefit for multiple di...

Approximately 95% of human genes are alternatively spliced, and aberrant splicing events can cause disease. One pre-mRNA that is alternatively spliced and linked to neurodegenerative diseases is tau (microtubule-associated protein tau), which can cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and can contribute to...

Tauopathies are neurodegenerative diseases that affect millions of people worldwide including those with Alzheimer’s disease. While many efforts have focused on understanding the role of tau protein in neurodegeneration, there has been little done to systematically analyze and study the structures within tau’s encoding RNA and their connection to d...

The MYC gene encodes a human transcription factor and proto-oncogene that is dysregulated in over half of all known cancers. To better understand potential post-transcriptional regulatory features affecting MYC expression, we analyzed secondary structures in the MYC mRNA using a program that is optimized for finding small locally-folded motifs with...

Aberrant RNA structure and function operate in neurological disease progression and severity. As RNA contributes to disease pathology in a complex fashion, that is, via various mechanisms, it has become an attractive therapeutic target for small molecules and oligonucleotides. In this review, we discuss the identification of RNA structures that cau...

Myotonic dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by an expanded CTG repeat that is transcribed into r(CUG) exp . The RNA repeat expansion sequesters regulatory proteins such as Muscleblind-like protein 1 (MBNL1), which causes pre-mRNA splicing defects. The disease-causing r(CUG) exp has been targeted by antisense oligon...

Tauopathies are neurodegenerative diseases that affect millions of people worldwide including those with Alzheimer's disease. While many efforts have focused on understanding the role of tau protein in neurodegeneration, there has been little done to systematically analyze and study the structures within tau's encoding RNA and their connection to d...

Rapid progress in genome sequencing technology has put us firmly into a postgenomic era. A key challenge in biomedical research is harnessing genome sequence to fulfill the promise of personalized medicine. This Review describes how genome sequencing has enabled the identification of disease-causing biomolecules and how these data have been convert...

RNA repeat expansions cause a host of incurable, genetically-defined diseases. The most common class of RNA repeats are trinucleotide repeats. These long, repeating transcripts fold into hairpins containing 1 × 1 internal loops that can mediate disease via a variety of mechanism(s) in which RNA is the central player. Two of these disorders are Hunt...

Dynamic programming methods for predicting RNA secondary structure often use thermodynamics and experimental restraints and/or constraints to limit folding space. Chemical mapping results typically restrain certain nucleotides not to be in AU or GC pairs. Two-dimensional nuclear magnetic resonance (NMR) spectra can reveal the order of AU, GC, and G...

Knowledge of RNA structure is necessary to determine structure-function relationships and to facilitate design of potential therapeutics. RNA secondary structure prediction can be improved by applying constraints from NMR experiments to a dynamic programming algorithm. Imino proton walks from NOESY spectra reveal double-stranded regions. Chemical s...

Influenza A is an RNA virus with a genome of eight negative sense segments. Segment 7 mRNA contains a 3' splice site for alternative splicing to code for essential M2 protein. On the basis of sequence alignment and chemical mapping experiments, the secondary structure surrounding the 3' splice site has an internal loop, adenine bulge, and hairpin l...

Thermodynamic parameters for GU pairs are important for predicting the secondary structures of RNA and for finding genomic sequences that code for structured RNA. Optical melting curves were measured for 29 RNA duplexes with GU pairs to improve nearest neighbor parameters for predicting stabilities of helixes. The updated model eliminates a prior p...

RNA has a large number of vital functions in the cell and sequencing of genomes is providing a huge database of RNA sequences. Experimental results can be combined with thermodynamics to help decode this database into secondary structures that identify targets for therapeutics. NMR can rapidly provide constraints for algorithms that predict seconda...

Many discoveries in the past 30 years have revealed an unexpected range of biological functions for RNA. This suggests that RNA will be an expanding target for therapeutics. Genome sequencing is providing an avalanche of RNA sequences. There is relatively little RNA structural information, however. The thermodynamics of RNA folding facilitates find...

Each segment of the influenza A virus (IAV) genome contains conserved sequences at the 5'- and 3'-terminal ends, which form the promoter region necessary for polymerase binding and initiation of RNA synthesis. Although several models of interaction have been proposed it remains unclear if these two short, partially complementary, and highly conserv...

The C2 conformation 3 was established to be the preferred conformation of the isopropyl cation. The calculated 13C NMR chemical shifts of C2 conformation 3 also agree very well with the experimental data. However, this is, in contrast with the recent claims by Fărcaşiu and coworkers, who found that the preferred conformation of the isopropyl cation...

The C(3h) conformation of the trimethylsilicenium ion 1 was established to be the preferred global energy minimum structure based on energy calculations. Because C-H hyperconjugation occurs least favorably in this conformation of the analogous tert-butyl cation, it may not contribute in large part to the stabilization of this cation, especially giv...

The C(s) conformation of the tert-butyl cation 3 was established to be the preferred global energy minimum using a combination of ab initio, DFT, and CCSD(T) methodology with correlation-consistent basis sets. The potential energy surface of methyl rotation involving the C(3v), C(s), and C(3h) forms, however, in accord with previous studies, is qui...