Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.2.1.1 (ACS)
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The development of small molecule chemical probes or therapeutics that target RNA remains a significant challenge despite the great interest in such compounds. The most significant barrier to compound development is defining which chemical and RNA motif spaces interact specifically. Herein, we describe a bioactive small molecule probe that targets expanded r(CGG) repeats, or r(CGG)(exp), that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium binds the 5'CGG/3'GGC motifs in r(CGG)(exp) and disrupts a toxic r(CGG)(exp)-protein complex in vitro. Structure-activity relationship studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG)(exp). Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)(exp)-containing nuclear foci. This approach may establish a general strategy to identify lead ligands that target RNA while also providing a chemical probe to dissect the varied mechanisms by which r(CGG)(exp) promotes toxicity.
ACS Chem Biol 2012 Oct 19
PMID:A small molecule that targets r(CGG)(exp) and improves defects in fragile X-associated tremor ataxia syndrome. 2294 43

We designed small molecules that bind the structure of the RNA that causes fragile X-associated tremor ataxia syndrome (FXTAS), an incurable neuromuscular disease. FXTAS is caused by an expanded r(CGG) repeat (r(CGG)(exp)) that inactivates a protein regulator of alternative pre-mRNA splicing. Our designed compounds modulate r(CGG)(exp) toxicity in cellular models of FXTAS, and pull-down experiments confirm that they bind r(CGG)(exp) in vivo. Importantly, compound binding does not affect translation of the downstream open reading frame (ORF). We compared molecular recognition properties of our optimal compound to oligonucleotides. Studies show that r(CGG)(exp)'s self-structure is a significant energetic barrier for oligonucleotide binding. A fully modified 2'-OMethyl phosphorothioate is incapable of completely reversing an FXTAS-associated splicing defect and inhibits translation of the downstream ORF, which could have deleterious effects. Taken together, these studies suggest that a small molecule that recognizes structure may be more well suited for targeting highly structured RNAs that require strand invasion by a complementary oligonucleotide.
ACS Chem Biol 2014 Apr 18
PMID:Targeting the r(CGG) repeats that cause FXTAS with modularly assembled small molecules and oligonucleotides. 2450 27

In polyglutamine (polyQ)-mediated disorders, the expansion of translated CAG repeats in the disease genes result in long polyQ tracts in their respective proteins, leading to intracellular accumulation of aggregated polyQ proteins, production of reactive oxygen species, and cell death. The molecular chaperones act in preventing protein misfolding and aggregation, thus inhibiting a wide range of harmful downstream events. In the circumstance of accumulation of aggregated polyQ proteins, the autophagic pathway is induced to degrade the misfolded or aggregated proteins. In this study, we used Flp-In 293/SH-SY5Y cells with inducible SCA3 ATXN3/Q75-GFP expression to test the effect of indole and synthetic derivatives for neuroprotection. We found that ATXN3/Q75 aggregation can be significantly prohibited in Flp-In 293 cells by indole and derivative NC001-8. Meanwhile, indole and NC001-8 up-regulated chaperones and autophagy in the same cell models. Both of them further promote neurite outgrowth in neuronal differentiated SH-SY5Y ATXN3/Q75-GFP cells. Our results demonstrate how indole and derivative NC001-8 are likely to work in reduction of polyQ-aggregation and provide insight into the possible effectual mechanism of indole compounds in polyQ spinocerebellar ataxia (SCA) patients. These findings may have therapeutic applications in a broad range of clinical situations.
ACS Chem Neurosci 2014 Oct 15
PMID:The potential of indole and a synthetic derivative for polyQ aggregation reduction by enhancement of the chaperone and autophagy systems. 2519 52

RNA transcripts containing expanded nucleotide repeats cause many incurable diseases via various mechanisms. One such disorder, fragile X-associated tremor ataxia syndrome (FXTAS), is caused by a noncoding r(CGG) repeat expansion (r(CGG)(exp)) that (i) sequesters proteins involved in RNA metabolism in nuclear foci, causing dysregulation of alternative pre-mRNA splicing, and (ii) undergoes repeat associated non-ATG translation (RANT), which produces toxic homopolymeric proteins without using a start codon. Here, we describe the design of two small molecules that inhibit both modes of toxicity and the implementation of various tools to study perturbation of these cellular events. Competitive Chemical Cross Linking and Isolation by Pull Down (C-Chem-CLIP) established that compounds bind r(CGG)(exp) and defined small molecule occupancy of r(CGG)(exp) in cells, the first approach to do so. Using an RNA GFP mimic, r(CGG)(exp)-Spinach2, we observe that our optimal designed compound binds r(CGG)(exp) and affects RNA localization by disrupting preformed RNA foci. These events correlate with an improvement of pre-mRNA splicing defects caused by RNA gain of function. In addition, the compounds reduced levels of toxic homopolymeric proteins formed via RANT. Polysome profiling studies showed that small molecules decreased loading of polysomes onto r(CGG)(exp), explaining decreased translation.
ACS Chem Biol 2016 09 16
PMID:Small Molecule Recognition and Tools to Study Modulation of r(CGG)(exp) in Fragile X-Associated Tremor Ataxia Syndrome. 2727 16

A (GGGGCC) hexanucleotide repeat (HR) expansion in the C9ORF72 gene has been considered the major cause behind both frontotemporal dementia and amyotrophic lateral sclerosis, while a (GGGCCT) is associated with spinocerebellar ataxia 36. Recent experiments involving NMR, CD, optical melting and 1D 1H NMR spectroscopy, suggest that the r(GGGGCC) HR can adopt a hairpin structure with G-G mismatches in equilibrium with a G-quadruplex structure. G-Quadruplexes have also been identified for d(GGGGCC). As these experiments lack molecular resolution, we have used molecular dynamics microsecond simulations to obtain a structural characterization of the G-quadruplexes associated with both HRs. All DNA G-quadruplexes, parallel or antiparallel, with or without loops are stable, while only parallel and one antiparallel (stabilized by diagonal loops) RNA G-quadruplexes are stable. It is known that antiparallel G-quadruplexes require alternating guanines to be in a syn conformation that is hindered by the C3'-endo pucker preferred by RNA. Initial RNA antiparallel quadruplexes built with C2'-endo sugars evolve such that the transition (C2'-endo)-to-(C3'-endo) triggers unwinding and buckling of the flat G-tetrads, resulting in the unfolding of the RNA antiparallel quadruplex. Finally, a parallel G-quadruplex stabilizes an adjacent C-tetrad in both DNA and RNA (thus effectively becoming a mixed quadruplex of 5 layers). The C-tetrad is stabilized by the stacking interactions with the preceding G-tetrad, by cyclical hydrogen bonds C(N4)-(O2), and by an ion between the G-tetrad and the C-tetrad. In addition, antiparallel DNA G-quadruplexes also stabilize flat C-layers at the ends of the quadruplexes.
ACS Chem Neurosci 2018 05 16
PMID:Structural and Dynamical Characterization of DNA and RNA Quadruplexes Obtained from the GGGGCC and GGGCCT Hexanucleotide Repeats Associated with C9FTD/ALS and SCA36 Diseases. 2928 Dec 54

Neurotoxicity is one major unwanted side-effects associated with polymyxin (i.e., colistin and polymyxin B) therapy. Clinically, colistin neurotoxicity is characterized by neurological symptoms including dizziness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, and facial and peripheral paresthesias. Pathologically, colistin-induced neurotoxicity is characterized by cell injury and death in neuronal cell. This Review covers our current understanding of polymyxin-induced neurotoxicity, its underlying mechanisms, and the discovery of novel neuroprotective agents to limit this neurotoxicity. In recent years, an increasing body of literature supports the notion that polymyxin-induced nerve damage is largely related to oxidative stress and mitochondrial dysfunction. P53, PI3K/Akt, and MAPK pathways are also involved in colistin-induced neuronal cell death. The activation of the redox homeostasis pathways such as Nrf2/HO-1 and autophagy have also been shown to play protective roles against polymyxin-induced neurotoxicity. These pathways have been demonstrated to be upregulated by neuroprotective agents including curcumin, rapamycin and minocycline. Further research is needed toward the development of novel polymyxin formulations in combination with neuroprotective agents to ameliorate this unwanted adverse effect during polymyxins therapy in patients.
ACS Chem Neurosci 2019 01 16
PMID:Molecular Mechanisms of Neurotoxicity Induced by Polymyxins and Chemoprevention. 3036 2

An expansion of CGG tandem repeats in the 5' untranslated region (5'-UTR) of fragile X mental retardation 1 (FMR1) gene causes fragile X-associated tremor/ataxia syndrome (FXTAS). The transcripts of these expanded repeats r(CGG)exp either form RNA foci or undergo the repeat-associated non-ATG (RAN) translation that produces toxic homopolymeric proteins in neuronal cells. The discovery of small molecule modulators that possess a strong binding affinity and high selectivity to these toxic expanded repeats RNA could be a promising therapeutic approach to cure the expanded repeat-associated neurological diseases. Therefore, here we sought to test the therapeutic potential of a natural alkaloid, piperine, by assessing its ability to bind and neutralize the toxicity of r(CGG)exp RNA motif. To accomplish this first, we have determined the affinity of piperine to r(CGG)exp RNA using fluorescence-based binding assay and isothermal titration calorimetry assay. These assays showed that piperine forms a thermodynamically favorable interaction with r(CGG)exp RNA with high selectivity to the G-rich RNA motif. Interaction of piperine with r(CGG)exp motif was further validated using several biophysical techniques such as CD, CD melting, NMR spectroscopy, and gel retardation assay. Moreover, piperine was also found to be effective for improving the r(CGG)exp associated splicing defects and RAN translation in a FXTAS cell model system. Our results effectively provided the evidence that piperine strongly interacts with r(CGG)exp RNA and could be used as a suitable candidate for therapeutic development against FXTAS.
ACS Chem Neurosci 2019 08 21
PMID:Piperine Modulates Protein Mediated Toxicity in Fragile X-Associated Tremor/Ataxia Syndrome through Interacting Expanded CGG Repeat (r(CGG)exp) RNA. 3126 35

With the ongoing pandemic of coronavirus disease (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), our knowledge of the pathogenesis of COVID-19 is still in its infancy. Almost every aspect of the pathogen remains largely unknown, ranging from mechanisms involved in infection transmission, interplay with the human immune system, and covert mechanisms of end-organ damage. COVID-19 has manifested itself worldwide with a syndromic appearance that is dominated by respiratory dysregulations. While clinicians are focused on correcting respiratory homeostasis, echoing the original SARS, SARS-CoV-2 is also invading other end-organs, which may not exhibit overt clinical features. Nervous system involvement was not initially considered to play a significant role in patients with COVID-19. However, since this viewpoint was initially published, multiple studies have been released regarding the possible neurovirulence of SARS-CoV-2. In our previous viewpoint, we implored our colleagues to recognize the covert tactics of SARS-CoV-2 and emphasized that symptoms like anosmia, dysgeusia, ataxia, and altered mental status could be early signs of the neurotropic potential of this virus. The past few weeks, after the viewpoint surfaced, it was noticed that it has enabled clinicians and healthcare professionals to compute the neurovirulence associated with SARS-CoV-2 in COVID-19 patients, as evidenced by very recently reported studies.
ACS Chem Neurosci 2020 05 06
PMID:Updates on What ACS Reported: Emerging Evidences of COVID-19 with Nervous System Involvement. 3234 22

Flexible and ultrasensitive biosensing platforms capable of detecting a large number of trinucleotide repeats (TNRs) are crucial for future technology development needed to combat a variety of genetic disorders. For example, trinucleotide CGG repeat expansions in the FMR1 gene can cause Fragile X syndrome (FXS) and Fragile X-associated tremor/ataxia syndrome (FXTAS). Current state-of-the-art technologies to detect repeat sequences are expensive, while relying on complicated procedures, and prone to false negatives. We reasoned that two-dimensional (2D) molybdenum sulfide (MoS2) surfaces may be useful for label-free electrochemical detection of CGG repeats due to its high affinity for guanine bases. Here, we developed a low-cost and sensitive wax-on-plastic electrochemical sensor using 2D MoS2 ink for the detection of CGG repeats. The ink containing few-layered MoS2 nanosheets was prepared and characterized using optical, electrical, electrochemical, and electron microscopic methods. The devices were characterized by electron microscopic and electrochemical methods. Repetitive CGG DNA was adsorbed on a MoS2 surface in a high cationic strength environment and the electrocatalytic current of the CGG/MoS2 interface was recorded using a soluble Fe(CN)6-3/-4 redox probe by differential pulse voltammetry (DPV). The dynamic range for the detection of prehybridized duplexes ranged from 1 aM to 100 nM with a 3.0 aM limit of detection. A detection range of 100 fM to 1 nM was recorded for surface hybridization events. Using this method, we were able to observe selectivity of MoS2 for CGG repeats and distinguish nonpathogenic from disease-associated repeat lengths. The detection of CGG repeat sequences on inkjet printable 2D MoS2 surfaces is a forward step toward developing chip-based rapid and label-free sensors for the detection of repeat expansion sequences.
ACS Appl Mater Interfaces 2020 Nov 18
PMID:Label-free Electrochemical Detection of CGG Repeats on Inkjet Printable 2D Layers of MoS2. 3315 Oct 65