Abstract
Conformationally preorganized peptide nucleic acids (PNAs) have been synthesized through backbone modifications at the γ-position, where R = alanine, valine, isoleucine, and phenylalanine side chains. The effects of these side-chains on the conformations and hybridization properties of PNAs were determined using a combination of CD and UV-Vis spectroscopic techniques. Our results show that the γ-position can accommodate varying degrees of sterically hindered side-chains, reaffirming the bimodal function of PNAs as the true hybrids of “peptides” and “nucleic acids.”
Highlights
Oligonucleotides are becoming increasingly important in the postgenomic era, as molecular tools for basic research as well as potential therapeutic and diagnostic reagents for the treatment and detection of genetic diseases [1,2,3,4]
A particular class of oligonucleotide analogue endowed with such synthetic flexibility is peptide nucleic acids (PNAs) [13]
We showed that randomly folded, single-stranded PNAs can be preorganized into either a right-handed or left-handed helix by installing Journal of Nucleic Acids an appropriate stereogenic center at the γ-backbone position [27,28,29]. γPNAs derived from L-amino acids adopted a right-handed helix, while those derived from D-amino acids adopted a left-handed helix; only the right-handed helical γPNAs are able to hybridize to DNA and RNA with high affinity and sequence selectivity
Summary
Oligonucleotides are becoming increasingly important in the postgenomic era, as molecular tools for basic research as well as potential therapeutic and diagnostic reagents for the treatment and detection of genetic diseases [1,2,3,4]. A number of amino acid side chains including alanine [22, 23], serine [27], cysteine [25], and lysine [24, 26, 30] have been incorporated at this position, a systematic study aimed at assessing the effect of steric hindrance on the conformations and hybridization properties of PNAs has not yet been established Knowledge of this information is crucial to the future design of PNAs with improved hybridization properties, water solubility, cellular uptake, biodistribution, and pharmacokinetics—all of which are essential for their in vivo applications.
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