Peptide nucleic acids (PNA) derived from N-(N-methylaminoethyl)glycine. Synthesis, hybridization and structural properties

Abstract

Backbone N-methylated peptide nucleic acids (PNAs) containing the four nucleobases adenine, cytosine, guanine and thymine were synthesized via solid phase peptide oligomerization. The oligomers bind to their complementary target with a thermal stability that is 1.5È4.5 ¡C lower per "" N-methyl nucleobase unit ÏÏ [dependent on the number and position(s) of the N-methyl] than that of unmodiÐed PNA. However, even fully N-methyl modiÐed PNAs bind as efficiently to DNA or RNA targets as DNA itself. Furthermore, the hybridization efficiency per N-methyl unit in a PNA decreased with increasing N-methyl content, and the e †ect was more pronounced when the N-methyl backbone units are present in the Hoogsteen versus the WatsonÈCrick strand in triplexes. (PNA) 2 -DNA Interestingly, CD spectral analyses indicate that 30% (3 out of ten) substitution with N-methyl nucleobases did not alter the structure of PNA-DNA (or RNA) duplexes or triplexes, and likewise CD spectroscopy and (PNA) 2 -DNA X-ray crystallography showed no major structural di †erences between N-methylated (30%) and unmodiÐed PNA-PNA duplexes. However, PNA-DNA duplexes as well as triplexes adopted a di †erent conformation when formed with all-N-methyl PNAs.

Insights into peptide nucleic acid (PNA) structural features: The crystal structure of a d -lysine-based chiral PNA–DNA duplex

“…The crystal structure of the (PNA) 2 -DNA triplex (10) also showed helical parameters significantly different from those of canonical DNA or RNA helical forms, defining a type of helix, named the P-helix, characterized by a small twist angle, a large x-displacement, and a wide, deep major groove. Finally, structural features of the PNA-PNA double helix (11)(12)(13) are similar to those of the P-helix mentioned above.…”

“…Water molecules located in the minor groove are also stabilized by H-bonds with nucleobases (purine-N3 or pyrimidine O2). In particular, those bound to the PNA strand form a bridge between the nucleobases and the amides of the backbone (N or O depending on the orientation of the amide bond), as observed for the PNA-PNA structure (11)(12)(13).…”

“…A PNA-RNA duplex (8) and a PNA-DNA duplex (9) were characterized by NMR in solution, whereas a (PNA) 2 -DNA triplex (10) and three PNA-PNA duplexes (11)(12)(13) were solved by x-ray crystallography. The structural analysis in solution of the PNA-DNA (9) and PNA-RNA duplexes (8) showed that PNA, when hybridized to RNA, adopts an A-like helix, whereas, when hybridized to a complementary DNA strand, it adopts a conformation that is different from both the A and the B forms.…”

Peptide Nucleic Acids (PNAs), A Chemical Overview

“…The secondary amides in an aegPNA backbone have been modified to a tertiary N-methyl amide, although moderate loss in binding to DNA is observed (94, Fig. 27) [130]. The work of Efimov et al elegantly showed that the secondary amides of a e g PNA can be replaced with a phosphonate or phosphonamide, again with moderate reduction in binding to DNA (95, Fig.…”

Design, Synthesis, and Hybridisation of Water‐Soluble, Peptoid Nucleic Acid Oligomers Tagged with Thymine

“…Furthermore, two enlightening studies on PNAs showing N γ alkylation, [19] indicated that the N-H H-bonding was not crucial for the stabilization of the PNA/nucleic acid double strand. Thus, we reasoned that N-alkylation of the backbone with polar groups, in a pure peptoid framework, could represent a novel strategy for a fine-tuning of PNA properties and provide a new way to overcome the pressing water-solubility issue.…”