A5017275370- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- RNA modifications and cancer
- Genetic Neurodegenerative Diseases
- RNA Interference and Gene Delivery
- Viral Infections and Immunology Research
- Advanced biosensing and bioanalysis techniques
- DNA and Nucleic Acid Chemistry
- MicroRNA in disease regulation
- Neurogenetic and Muscular Disorders Research
- Amyotrophic Lateral Sclerosis Research
- CRISPR and Genetic Engineering
- Genetics and Neurodevelopmental Disorders
- Bacteriophages and microbial interactions
- RNA regulation and disease
- Monoclonal and Polyclonal Antibodies Research
- Mitochondrial Function and Pathology
- Glycosylation and Glycoproteins Research
- Cardiomyopathy and Myosin Studies
- Protein Degradation and Inhibitors
- Chemical Synthesis and Analysis
- Advanced Biosensing Techniques and Applications
- Cancer-related molecular mechanisms research
- Carbohydrate Chemistry and Synthesis
- Bacterial Genetics and Biotechnology
Scripps Research Institute
2016-2025
Scripps (United States)
2012-2025
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
2023-2025
Indivior (United States)
2024
Hebrew University of Jerusalem
2022
University of Florida
2022
Jupiter Medical Center
2020
Florida Atlantic University
2017
Scripps Institution of Oceanography
2012-2014
University of Rochester
1999-2014
A dynamic programming algorithm for prediction of RNA secondary structure has been revised to accommodate folding constraints determined by chemical modification and include free energy increments coaxial stacking helices when they are either adjacent or separated a single mismatch. Furthermore, parameters account recent experimental results terminal mismatches hairpin, bulge, internal, multibranch loops. To demonstrate the applicability this method, in vivo was performed on 5S rRNA both...
Many pathogens that infect humans use cell surface carbohydrates as receptors to facilitate cell−cell adhesion. The hallmark of these interactions is their multivalency, or the simultaneous occurrence multiple interactions. We have used a carbohydrate-functionalized fluorescent polymer, which displays many carbohydrate ligands on single polymer chain, allow for multivalent detection pathogens. Incubation mannose-functionalized with Escherichia coli yields brightly aggregates bacteria. These...
Repeat Silencing Fragile X syndrome, a genetic cause of many cases autism and mental retardation, involves expansion trinucleotide repeat in the fragile retardation 1 (FMR1) gene. Working with human embryonic stem cells, Colak et al. (p. 1002 ) found that expanded region was transcribed into untranslated FMR1 messenger RNA, which then bound to DNA gene, inactivating The findings explain how causes RNA-directed gene silencing during development syndrome.
Poly(GP) proteins are a promising pharmacodynamic marker for developing and testing therapeutics treating C9ORF72 -associated amyotrophic lateral sclerosis.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by the expansion of 55-200 CGG repeats in 5 0 UTR FMR1.These expanded are transcribed and accumulate nuclear RNA aggregates that sequester one or more RNA-binding proteins, thus impairing their functions.Here, we have identified double-stranded RNAbinding protein DGCR8 binds to repeats, resulting partial sequestration its partner, DROSHA, within aggregates.Consequently, processing micro-RNAs...
The development of small molecules that target RNA is challenging yet, if successful, could advance the chemical probes to study function or precision therapeutics treat RNA-mediated disease. Previously, we described Inforna, an approach can mine motifs (secondary structures) within RNAs, which deduced from sequence, and compare them a database known motif-small molecule binding partners. Output generated by Inforna includes motif found in both desired target, lead for other related...
The biology of healthy and disease-affected cells is often mediated by RNA structures, desirable targets for small molecule chemical probes lead medicines. Although structured regions are found throughout the transcriptome, some even with demonstrated functionality, human RNAs considered recalcitrant to targeting. However, targeting molecules provides an important alternative oligonucleotides that target sequence. In this Perspective, we describe challenges progress in developing interacting...
Significance The goal of precision medicine is to identify selective drugs that modulate disease-causing biomolecules. This slow process often involves developing a high-throughput screen test millions potential find few affect the biomolecule. Here, we describe facile approach using biomolecule’s sequence enable design specific drugs, eliminating arduous and time-consuming screens. By non–protein-coding, oncogenic RNA, designed drug specifically targeting RNA’s folded structure. In cells...
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...
The choreography between RNA synthesis and degradation is a key determinant in biology. Engineered systems such as CRISPR have been developed to rid cell of RNAs. Here, we show that small molecule can recruit nuclease specific transcript, triggering its destruction. A selectively binds the oncogenic microRNA(miR)-96 hairpin precursor was appended with short 2′-5′ poly(A) oligonucleotide. conjugate locally activated endogenous, latent ribonuclease (RNase L), which cleaved miR-96 cancer cells...
As the area of small molecules interacting with RNA advances, general routes to provide bioactive compounds are needed as ligands can bind avidly sites that will not affect function. Small-molecule targeted degradation thus a route biology. A non–oligonucleotide-containing compound was designed from sequence target precursor oncogenic microRNA-21 (pre–miR-21) for enzymatic destruction selectivity exceed protein-targeted medicines. The specifically binds and contains heterocycle recruits...
Abstract Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding molecular recognition of RNA structures small molecules. Here we studied patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded structures. Mapping these interaction landscapes across human transcriptome defined structure–activity relationships. Although RNA-binding compounds that bind...
α-Synuclein is an important drug target for the treatment of Parkinson’s disease (PD), but it intrinsically disordered protein lacking typical small-molecule binding pockets. In contrast, encoding SNCA mRNA has regions ordered structure in its 5′ untranslated region (UTR). Here, we present integrated approach to identify small molecules that bind this structured and inhibit α-synuclein translation. A drug-like, RNA-focused compound collection was studied UTR mRNA, affording Synucleozid-2.0,...
There is a keen interest in developing techniques for rapid genetic analysis that do not require labeling of an analyte. Here we demonstrate fluorophore-tagged DNA hairpins attached to gold films can function as immobilized "molecular beacons". Two incorporating portions the Staphlococcus aureus FemA and mecR methicillin-resistance genes were substrate. Upon exposure complement, ∼26-fold increase fluorescence intensity was measured corresponding 96 ± 5% quenching efficiency. Studies with...
Herein, we describe the design of high affinity ligands that bind expanded rCUG and rCAG repeat RNAs expressed in myotonic dystrophy type 1 (DM1) spinocerebellar ataxia 3. These also inhibit, with nanomolar IC50 values, formation RNA−protein complexes are implicated both disorders. The repeats form stable RNA hairpins regularly repeating internal loops stem have deleterious effects on cell function. display a derivative bisbenzimidazole Hoechst 33258, which was identified by searching known...
A hypoxic state is critical to the metastatic and invasive characteristics of cancer. Numerous pathways play roles in cancer maintenance, many which include noncoding RNAs such as microRNA (miR)-210 that regulates hypoxia inducible factors (HIFs). Herein, we describe identification a small molecule named Targapremir-210 binds Dicer site miR-210 hairpin precursor. This interaction inhibits production mature miRNA, derepresses glycerol-3-phosphate dehydrogenase 1-like enzyme (GPD1L),...