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Chapter 6
Figure 6-2: A standard PNA compared with a 2S,5S-modified PNA: both
are able to perform DNA recognition, but the backbone of the latter has
also the potential to mimic a peptide sequence
Although the introduction of substituents in the PNA backbone have been used in order to
introduce functional groups and charges (thus modulating the properties of PNA) 27,28,29 , the
use of side chains mimicking an entire complex peptide consensus sequence with a specific
biological function has never been reported, and represents a challenging task both
conceptually and synthetically. The possibility to develop a PNA able to act as a mimic of
NLS peptide, would allow the PNA to enter a cell, recognize importin α protein, enter the
nucleus, and perform its antigene activity without the need to couple the molecule to any cell
penetrating peptide. In this chapter the design and the synthesis of a modified model PNA
embedding in its backbone a mimic of a Nuclear Localization Signal (NLS) is reported,
together with preliminary studies on its ability to penetrate cell nuclei.
As reported in the introduction (chapter 1), the correct configurations for having right-handed
PNAs, thus able to efficiently bind complmentary DNA, in 2,5 substituted PNAs have been
found to be 2D,5L and 2L,5L. Thus, a backbone including L-amino acid-derived side chains
at positions 2 and 5 (Figure 6-2) has the potential to be a good mimic of natural peptides,
formed by all L-amino acids, at the same time preserving the correct handedness for DNA
binding.
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