Open AccessThe 2-Aminopyridine Nucleobase Improves Triple-Helical Recognition of RNA and DNA When Used Instead of Pseudoisocytosine in Peptide Nucleic Acids
Author(s) -
C.A. Ryan,
Nikita Brodyagin,
Justin Lok,
Eriks Rozners
Publication year - 2021
Publication title -
biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.43
H-Index - 253
eISSN - 1520-4995
pISSN - 0006-2960
DOI - 10.1021/acs.biochem.1c00275
Subject(s) - nucleobase , nucleic acid , dna , chemistry , rna , peptide , cytosine , selectivity , nucleic acid structure , binding selectivity , nucleic acid analogue , protonation , stereochemistry , combinatorial chemistry , biochemistry , nucleic acid thermodynamics , base sequence , gene , organic chemistry , ion , catalysis
Pseudoisocytosine (J), a neutral analogue of protonated cytosine, is currently the gold standard modified nucleobase in peptide nucleic acids (PNAs) for the formation of J·G-C triplets that are stable at physiological pH. This study shows that triple-helical recognition of RNA and DNA is significantly improved by using 2-aminopyridine (M) instead of J. The positively charged M forms 3-fold stronger M+·G-C triplets than J with uncompromised sequence selectivity. Replacement of six Js with Ms in a PNA 9-mer increased its binding affinity by ∼2 orders of magnitude. M-modified PNAs prefer binding double-stranded RNA over DNA and disfavor off-target binding to single-stranded nucleic acids. Taken together, the results show that M is a promising modified nucleobase that significantly improves triplex-forming PNAs and may provide breakthrough developments for therapeutic and biotechnology applications.