Helical Peptide Nucleic Acids aPNAs

Recently, the related phenomenon of RNA interference (RNAi) has attracted much attention [5]. RNAi occurs when a short (generally 21 nucleotides in length) double-stranded RNA (dsRNA) catalyticaUy represses the translation of a fully complementary mRNA sequence. The process appears to proceed via a complex formed between the antisense RNA strand and a protein with RNase activity [6]. Upon binding to the target mRNA sequence, the ribonucleoprotein complex initiates cleavage of the mRNA transcript thus preventing translation of intact protein. After dissociation from the truncated mRNAs, the ribonucleoprotein complex is free to act on other intact mRNAs. Such small interfering RNAs (siRNAs) have 

The fundamental a-hehcal peptide nucleic acid (aPNA) concept is illustrated in Fig. 5.2. Our prototype aPNA module incorporated five nucleobases for Watson-Crick base pairing with a single-stranded nucleic acid target. These nucleobases 

1) Amino acid abbreviations aa, generic amino acid Ala, L-alanine Aib, 2-aminoisobutyric acid Cys, L-cysteine Asp, L-aspartic acid Glu, L-glutamic acid Gly, glycine Lys, L-ly-sine Ser, L-serine Trp, L-tryptophan Ser, 2-amino-3-(5-methyl-2,4-dioxo-3,4-dihydro-2H- 

N-eap helix dipole salt bridge salt bridge extra helix helix dipole C-cap stabili ation stability stabiiization 

N-cap amine amine amine amine amine amine C-cap 

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Fig. 5.2 The a-helical peptide nucleic acid (aPNA) design concept. (Reprinted with permission from Garner P., Dey S., Huang Y.J. Am. Chem. Soc. 2000, 722, 2405 [51])...

These studies showed thaL in the absence of nucleic acid, the backbone 1 aPNA had significant a-hehcal content at pH 7 whereas the backbone 2 aPNA was largely in a random coil conformation at physiological pH. The latter aPNA did become a-helical at higher pHs in a manner reminiscent of the structurally related amphipathic peptides. 

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