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Photoswitchable Oligonucleotides Containing Different Diarylethene-Modified Nucleotides.

ABSTRACT: Diarylethenes are a well-studied class of photoswitches and have often been linked to partner molecules to render them photoresponsive. Earlier, our lab developed a new type of diarylethenes in which the purine or pyrimidine base of a nucleoside or oligonucleotide serves as one of the two aryl residues of the photochromic system. Here, we report the synthesis of three different diarylethene-deoxyuridine phosphoramidites and their site-specific incorporation into oligodeoxynucleotides by solid-phase synthesis. Various DNA sequences carrying single or multiple, identical or different photoswitchable moieties are synthesized with high yield and purity. Upon UV irradiation, these DNA strands form a colored closed-ring isomer. The combination of different diarylethenes within one strand leads to an additive absorption spectrum. The photochromic DNA oligonucleotides are thermostable and photoreversible.

SUBMITTER: Sarter C

PROVIDER: S-EPMC6682051 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Photoswitchable Oligonucleotides Containing Different Diarylethene-Modified Nucleotides.

Sarter Christopher C Dey Surjendu S Jäschke Andres A

ACS omega 20190715 7

Diarylethenes are a well-studied class of photoswitches and have often been linked to partner molecules to render them photoresponsive. Earlier, our lab developed a new type of diarylethenes in which the purine or pyrimidine base of a nucleoside or oligonucleotide serves as one of the two aryl residues of the photochromic system. Here, we report the synthesis of three different diarylethene-deoxyuridine phosphoramidites and their site-specific incorporation into oligodeoxynucleotides by solid-ph ...[more]

PMID: 31460326

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Project description:UNLABELLED:Invading pathogen nucleic acids are recognized and bound by cytoplasmic (retinoic acid-inducible gene I [RIG-I]-like) and membrane-bound (Toll-like) pattern recognition receptors to activate innate immune signaling. Modified nucleotides, when present in RNA molecules, diminish the magnitude of these signaling responses. However, mechanisms explaining the blunted signaling have not been elucidated. In this study, we used several independent biological assays, including inhibition of virus replication, RIG-I:RNA binding assays, and limited trypsin digestion of RIG-I:RNA complexes, to begin to understand how RNAs containing modified nucleotides avoid or suppress innate immune signaling. The experiments were based on a model innate immune activating RNA molecule, the polyU/UC RNA domain of hepatitis C virus, which was transcribed in vitro with canonical nucleotides or with one of eight modified nucleotides. The approach revealed signature assay responses associated with individual modified nucleotides or classes of modified nucleotides. For example, while both N-6-methyladenosine (m6A) and pseudouridine nucleotides correlate with diminished signaling, RNA containing m6A modifications bound RIG-I poorly, while RNA containing pseudouridine bound RIG-I with high affinity but failed to trigger the canonical RIG-I conformational changes associated with robust signaling. These data advance understanding of RNA-mediated innate immune signaling, with additional relevance for applying nucleotide modifications to RNA therapeutics. IMPORTANCE:The innate immune system provides the first response to virus infections and must distinguish between host and pathogen nucleic acids to mount a protective immune response without activating autoimmune responses. While the presence of nucleotide modifications in RNA is known to correlate with diminished innate immune signaling, the underlying mechanisms have not been explored. The data reported here are important for defining mechanistic details to explain signaling suppression by RNAs containing modified nucleotides. The results suggest that RNAs containing modified nucleotides interrupt signaling at early steps of the RIG-I-like innate immune activation pathway and also that nucleotide modifications with similar chemical structures can be organized into classes that suppress or evade innate immune signaling steps. These data contribute to defining the molecular basis for innate immune signaling suppression by RNAs containing modified nucleotides. The results have important implications for designing therapeutic RNAs that evade innate immune detection.

Dataset Information

Photoswitchable Oligonucleotides Containing Different Diarylethene-Modified Nucleotides.

Publications

Photoswitchable Oligonucleotides Containing Different Diarylethene-Modified Nucleotides.

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