A5080126683- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Genetic Neurodegenerative Diseases
- RNA regulation and disease
- Neurogenetic and Muscular Disorders Research
- Viral Infections and Immunology Research
- Mitochondrial Function and Pathology
- Protein Structure and Dynamics
- Amyotrophic Lateral Sclerosis Research
- DNA and Nucleic Acid Chemistry
- Cancer-related molecular mechanisms research
- HIV/AIDS drug development and treatment
- Peptidase Inhibition and Analysis
- interferon and immune responses
- CRISPR and Genetic Engineering
- Pneumocystis jirovecii pneumonia detection and treatment
- Influenza Virus Research Studies
- Cytomegalovirus and herpesvirus research
- Advanced biosensing and bioanalysis techniques
- Genetics and Neurodevelopmental Disorders
- SARS-CoV-2 and COVID-19 Research
- Ubiquitin and proteasome pathways
- Retinal Development and Disorders
- Bacterial Genetics and Biotechnology
University of Rochester Medical Center
2018-2024
Scripps Research Institute
2017-2024
University of Rochester
2011-2018
COVID-19 is a global pandemic, thus requiring multiple strategies to develop modalities against it. Herein, we designed bioactive small molecules that target functional structure within the SARS-CoV-2's RNA genome, causative agent of COVID-19. An analysis characterize genome provided revised model SARS-CoV-2 frameshifting element, in particular its attenuator hairpin. By studying an RNA-focused molecule collection, identified drug-like (C5) avidly binds hairpin with Kd 11 nM. The compound...
Myotonic dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by expanded CTG repeat that transcribed into r(CUG) exp . The RNA expansion sequesters regulatory proteins such as Muscleblind-like protein (MBNL1), which causes pre-mRNA splicing defects. disease-causing has been targeted antisense oligonucleotides, CRISPR-based approaches, and RNA-targeting small molecules. Herein, we describe a designer molecule, Cugamycin, recognizes the structure of cleaves it in both DM1...
Small-molecule recruitment of an endogenous nuclease rescues pathologies associated with c9ALS/FTD in vivo by targeting RNA repeat expansion.
Thermodynamic parameters for GU pairs are important predicting the secondary structures of RNA and finding genomic sequences that code structured RNA. Optical melting curves were measured 29 duplexes with to improve nearest neighbor stabilities helixes. The updated model eliminates a prior penalty assumed terminal pairs. Six additional 5′GG/3′UU motif added single representation in previous database. This revises ΔG°37 from an unfavorable 0.5 kcal/mol favorable −0.2 kcal/mol. Similarly,...
Approximately 95% of human genes are alternatively spliced, and aberrant splicing events can cause disease. One pre-mRNA that is spliced linked to neurodegenerative diseases tau (microtubule-associated protein tau), which frontotemporal dementia parkinsonism chromosome 17 (FTDP-17) contribute Alzheimer's Here, we describe the design structure-specific lead small molecules directly target from sequence. This was followed by hit expansion analogue synthesis further improve upon these initial...
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, inclusion which encodes for a toxic harboring four microtube domains (4R tau). Here, we describe design an RNA-targeted small molecule that thermodynamically stabilizes structure regulator element in MAPT 10-intron junction reduce 10 and hence 4R abundance. Structure-based drug was used obtain compounds form...
RNA repeat expansions cause a host of incurable, genetically defined diseases. The most common class repeats consists trinucleotide repeats. These long, repeating transcripts fold into hairpins containing 1 × internal loops that can mediate disease via variety mechanism(s) in which is the central player. Two these disorders are Huntington's and myotonic dystrophy type 1, caused by r(CAG) r(CUG) repeats, respectively. We report structures two constructs three copies [r(3×CAG)] or [r(3×CUG)]...
RNA folding free energy change nearest neighbor parameters are widely used to predict stabilities of secondary structures. They were determined by linear regression datasets optical melting experiments on small model systems. Traditionally, the analyzed assuming a two-state model, i.e. structure is either complete or denatured. Experimental evidence, however, shows that structures exist in an ensemble conformations. Partition functions calculated with existing can be partially denatured,...
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 expression, we analyzed secondary structures the mRNA using program optimized for finding small locally-folded motifs with high propensity function. This was accomplished by calculating folding metrics across sequence sliding analysis window generating unique consensus base pairing models...
Influenza A is an RNA virus with a genome of eight negative sense segments. Segment 7 mRNA contains 3' splice site for alternative splicing to encode the essential M2 protein. On basis sequence alignment and chemical mapping experiments, secondary structure surrounding has internal loop, adenine bulge, hairpin loop when it in conformation that exposes site. We report structural features three-dimensional model derived from nuclear magnetic resonance spectra simulated annealing restrained...
Myotonic dystrophy type 2 (DM2) is one of >40 microsatellite disorders caused by RNA repeat expansions. The DM2 expansion, r(CCUG)exp (where "exp" denotes expanded repeating nucleotides), harbored in intron 1 the CCHC-type zinc finger nucleic acid binding protein (CNBP). causes disease a gain-of-function mechanism, sequestering various RNA-binding proteins including pre-mRNA splicing regulator MBNL1. Sequestration MBNL1 results its loss-of-function and concomitant deregulation alternative...
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, spinocerebellar ataxias. One approach for treating these is to bind small molecules structured RNAs. Both disease-like 2 (HDL2) dystrophy type 1 (DM1) are caused by r(CUG) expansion, or
Each segment of the influenza A virus (IAV) genome contains conserved sequences at 5'- and 3'-terminal ends, which form promoter region necessary for polymerase binding initiation RNA synthesis. Although several models interaction have been proposed it remains unclear if these two short, partially complementary, highly can a stable duplex physiological temperatures. First, our time-resolved FRET analysis revealed that 14-mer 3'-RNA 15-mer 5'-RNA associate in solution, even 42 °C. We also...
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 tau protein in neurodegeneration, there has been little done to systematically analyze and study structures within tau’s encoding RNA their connection disease pathology. Knowledge structure can provide insights into mechanisms how production for therapeutic benefit. Using computational methods based...
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 mechanisms. Herein, we identified a benzimidazole derivative, CB096, that specifically binds to repeating 1 × GG internal loop structure, 5′CGG/3′GGC,...
Knowledge of RNA structure is necessary to determine structure-function relationships and facilitate design potential therapeutics. secondary prediction can be improved by applying constraints from nuclear magnetic resonance (NMR) experiments a dynamic programming algorithm. Imino proton walks NOESY spectra reveal double-stranded regions. Chemical shifts protons in GH1, UH3, UH5 GU pairs, UH5, AH2 AU GH1 GC pairs were analyzed identify for the 5' 3' directionality base helices. The...