Open AccessPyridazine Nucleobase in Triplex-Forming PNA Improves Recognition of Cytosine Interruptions of Polypurine Tracts in RNA
Author(s) -
Nikita Brodyagin,
Ilze Kumpiņa,
Justin Applegate,
Mārtiņš Katkevičs,
Eriks Rozners
Publication year - 2021
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.1c00044
Subject(s) - nucleobase , rna , cytosine , triple helix , dna , base pair , guanine , nucleic acid , recognition sequence , molecular recognition , duplex (building) , computational biology , biology , chemistry , genetics , nucleotide , stereochemistry , gene , molecule , organic chemistry , restriction enzyme
Sequence specific recognition of regulatory noncoding RNAs would open new possibilities for fundamental science and medicine. However, molecular recognition of such complex double-stranded RNA (dsRNA) structures remains a formidable problem. Recently, we discovered that peptide nucleic acids (PNAs) form an unusually stable and sequence-specific triple helix with dsRNA. Triplex-forming PNAs could become universal tools for recognition of noncoding dsRNAs but are limited by the requirement of polypurine tracts in target RNAs as only purines form stable Hoogsteen hydrogen bonded base triplets. Herein, we systematically surveyed simple nitrogen heterocycles P N as modified nucleobases for recognition of cytosine in P N *C-G triplets. We found that a 3-pyridazinyl nucleobase formed significantly more stable P N *C-G triplets than other heterocycles including the pyrimidin-2-one previously used by us and others for recognition of cytosine interruptions in polypurine tracts of PNA-dsRNA triplexes. Our results improve triple helical recognition of dsRNA and provide insights for future development of new nucleobases to expand the sequence scope of noncoding dsRNAs that can be targeted by triplex-forming PNAs.