2 research outputs found
Design of a āMiniā Nucleic Acid Probe for Cooperative Binding of an RNA-Repeated Transcript Associated with Myotonic Dystrophy Type 1
Toxic
RNAs containing expanded trinucleotide repeats are the cause
of many neuromuscular disorders, one being myotonic dystrophy type
1 (DM1). DM1 is triggered by CTG-repeat expansion in the 3ā²-untranslated
region of the <i>DMPK</i> gene, resulting in a toxic gain
of RNA function through sequestration of MBNL1 protein, among others.
Herein, we report the development of a relatively short miniPEG-Ī³
peptide nucleic acid probe, two triplet repeats in length, containing
terminal pyrene moieties, that is capable of binding rCUG repeats
in a sequence-specific and selective manner. The newly designed probe
can discriminate the pathogenic rCUG<sup>exp</sup> from the wild-type
transcript and disrupt the rCUG<sup>exp</sup>āMBNL1 complex.
The work provides a proof of concept for the development of relatively
short nucleic acid probes for targeting RNA-repeat expansions associated
with DM1 and other related neuromuscular disorders
Design of Bivalent Nucleic Acid Ligands for Recognition of RNA-Repeated Expansion Associated with Huntingtonās Disease
We
report the development of a new class of nucleic acid ligands
that is comprised of Janus bases and the MPĪ³PNA backbone and
is capable of binding rCAG repeats in a sequence-specific and selective
manner via, inference, bivalent H-bonding interactions. Individually,
the interactions between ligands and RNA are weak and transient. However,
upon the installation of a C-terminal thioester and an N-terminal
cystine and the reduction of disulfide bond, they undergo template-directed
native chemical ligation to form concatenated oligomeric products
that bind tightly to the RNA template. In the absence of an RNA target,
they self-deactivate by undergoing an intramolecular reaction to form
cyclic products, rendering them inactive for further binding. The
work has implications for the design of ultrashort nucleic acid ligands
for targeting rCAG-repeat expansion associated with Huntingtonās
disease and a number of other related neuromuscular and neurodegenerative
disorders