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Naphthyridine tetramer with a pre-organized structure for 1:1 binding to a CGG/CGG sequence.

ABSTRACT: A naphthyridine carbamate dimer (NCD) is a synthetic ligand for DNA containing a CGG/CGG sequence. Although NCD can bind selectively and tightly to a CGG/CGG sequence, the highly cooperative 2:1 binding mode has hampered precise analysis of the binding. We describe herein the synthesis of a series of naphthyridine tetramers consisting of two NCD molecules connected with various linkers to seek a ligand that binds to a CGG/CGG sequence exclusively with a 1:1 stoichiometry. Among the tested ligands, NCTB and Z-NCTS, which have linker moieties with restricted conformational flexibility [biphenyl and (Z)-stilbene linker, respectively], gave the exclusive formation of a 1:1 ligand-CGG/CGG complex. The (Z)-stilbene linker in Z-NCTS was designed to have pre-organized conformation appropriate for the binding and, in fact, resulted in the highest binding affinity. Thermodynamic parameters obtained by isothermal titration calorimetry indicated that the stronger binding of Z-NCTS was attributed to its lower entropic cost. The present study provides not only a novel 1:1 binding ligand, but also valuable feedback for subsequent molecular design of DNA and RNA binding ligands.

PROVIDER: S-EPMC3315301 | BioStudies |

REPOSITORIES: biostudies

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Cyclic mismatch binding ligands interact with disease-associated CGG trinucleotide repeats in RNA and suppress their translation.

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Project description:Synthetic small molecules modulating RNA structure and function have therapeutic potential for RNA diseases. Here we report our discovery that naphthyridine carbamate dimer (NCD) targets disease-causing r(UGGAA)n repeat RNAs in spinocerebellar ataxia type 31 (SCA31). Structural analysis of the NCD-UGGAA/UGGAA complex by nuclear magnetic resonance (NMR) spectroscopy clarifies the mode of binding that recognizes four guanines in the UGGAA/UGGAA pentad by hydrogen bonding with four naphthyridine moieties of two NCD molecules. Biological studies show that NCD disrupts naturally occurring RNA foci built on r(UGGAA)n repeat RNA known as nuclear stress bodies (nSBs) by interfering with RNA-protein interactions resulting in the suppression of nSB-mediated splicing events. Feeding NCD to larvae of the Drosophila model of SCA31 alleviates the disease phenotype induced by toxic r(UGGAA)n repeat RNA. These studies demonstrate that small molecules targeting toxic repeat RNAs are a promising chemical tool for studies on repeat expansion diseases.

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SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity.

Project description:Transcribed CGG repeat expansions cause neurodegeneration in Fragile X-associated tremor/ataxia syndrome (FXTAS). CGG repeat RNAs sequester RNA-binding proteins (RBPs) into nuclear foci and undergo repeat-associated non-AUG (RAN) translation into toxic peptides. To identify proteins involved in these processes, we employed a CGG repeat RNA-tagging system to capture repeat-associated RBPs by mass spectrometry in mammalian cells. We identified several SR (serine/arginine-rich) proteins that interact selectively with CGG repeats basally and under cellular stress. These proteins modify toxicity in a Drosophila model of FXTAS. Pharmacologic inhibition of serine/arginine protein kinases (SRPKs), which alter SRSF protein phosphorylation, localization, and activity, directly inhibits RAN translation of CGG and GGGGCC repeats (associated with C9orf72 ALS/FTD) and triggers repeat RNA retention in the nucleus. Lowering SRPK expression suppressed toxicity in both FXTAS and C9orf72 ALS/FTD model flies, and SRPK inhibitors suppressed CGG repeat toxicity in rodent neurons. Together, these findings demonstrate roles for CGG repeat RNA binding proteins in RAN translation and repeat toxicity and support further evaluation of SRPK inhibitors in modulating RAN translation associated with repeat expansion disorders.

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SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity

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cis,trans-Dicarbonyl-dichlorido[2-(2-pyrid-yl)-1,8-naphthyridine-?N,N]ruthenium(II).

Project description:The asymmetric unit of the title compound, [RuCl(2)(C(13)H(9)N(3))(CO)(2)], consists of four crystallographically independent Ru(II) complexes. Each Ru(II) atom is in a distorted octa-hedral environment coordinated by two carbonyl ligands, two Cl atoms and a chelating 2-(2-pyrid-yl)-1,8-naphthyridine (pynp) ligand. The carbonyl ligands are cis to each other, while the Cl atoms are trans. Relatively short inter-atomic distances (2.60-2.67?Å) between the uncoordinated N atom of pynp and the C atom of the carbonyl imply a donor-acceptor inter-action between the pynp and carbonyl ligands.

2008-01-01 | S-EPMC2960803 | BioStudies

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