Polyamide nucleic acids

Lee R., Kaushik N., Modak M.J., Vi-NAYAK R., Pandey V. N. Polyamide nucleic acid targeted to the primer binding site of the HlV-1 RNA genome blocks in vitro HlV-1 reverse transcription. Biochemistry 1998 37 900-910. 

Nickols NG, Jacobs CS, Farkas ME, Dervan PB. Improved nuclear localization of DNA-binding polyamides. Nucleic Acids Res. 2007 35 363-370. 

Will, D. W., Breipohl, G., Langner, D., et al. (1995) The synthesis of polyamide nucleic acids using a novel monomethoxytrityl protecting-group strategy. Tetrahedron, 51, 12069-12082. 

Peptide (or polyamide) nucleic acid (PNA) is one of the candidates for diagnostic and therapeutic applications in medicine of the 21st century [375-377]. 

PepNAs are achiral and insensitive to CD, but optically pure polyamide nucleic acid analogues were also reported. Monomer 28 (Scheme 8) has naturally occurring amino acid units, which will confer chirality on the resulting polymers [65]. Although stereocenters on the backbones were expected to influence the complexation of the PepNAs, no details were reported. Polymer 29... 

A polyamide nucleic acid chimeric molecule has been computer modeled by Nielsen et al. by replacing the deoxyribose phosphate backbone of DNA through an achiral polyamide backbone (39). The new backbone, supposed to be homomorphous to DNA, consists of aminoethylgylcine units, which can be regarded as reduced diglycine. Since the nucleobase is connected to the backbone via nitrogen, the... 

Fig 19 Synthesis of polyamide nucleic acids (PNA). (A) Generation of a monomeric thyminyl building block. (B) Coupling of the monomer to the solid support. (C) Merrifield synthesis using Boc-strategy. (Boc = tert-butoxy carbonyl, Pfp = pentafluoro phenyl, S = 4-methylbenzhydrylamine resin)... 

Yet another type of polyamide nucleic acids analogs with a poly-L-lysine backbone (Fig. 20c, w = 4, z = 3) was described by Takemoto et al. (37). The ribose units in this analog mainly served the purpose of enhancing solubility of the polymers in water by the free hydroxy groups. For their preparation, 2 3 -0-isopropylidene-5 -0-glutaric acid succinimido nucleosides were coupled to prepolymerized L-lysine, a procedure not allowing sequence-specific introduction of nucleobases. 

There are approximately 20 common naturally occurring amino acids, hence 20 different R groups that appear as pendents on the polyamide chain. Many other amino acids have been isolated or prepared, each representing a variation in R. The number of isomeric stmctures is myriad. Protein biosynthesis is mediated by other biopolymers, the nucleic acids. 

The development of the aminoethylglycine polyamide (peptide) backbone oligomer with pendant nucleobases linked to the glycine nitrogen via an acetyl bridge now often referred to by PNA (peptide nucleic acid Fig. 4.1), was inspired... 

Nielsen P.E., Egholm M., Berg R. H., Buchardt O. Peptide nucleic acids (PNA) oligonucleotide analogs with a polyamide backbone. In Antisense Research and Applications. Crooke S.T., Le-BLBu B. (Eds). CRC Press, Boca Raton,... 

Kaushik N., Talele T.T., Monel R., Palumbo P., Pandey V.N. Destabilization of tRNA3Lys from the primer-binding site of HIV-1 genome by anti-A loop polyamide nucleotide analog. Nucleic Acids Res. 2001 29 5099-5106. 

This field has also inspired the development of a range of pseudo-peptides, that is polyamides composed of amino acids other than a-amino acids. These include for instance peptoids, /9-amino acid oligomers and also compounds such as peptide nucleic acids and DNA binding polyamides, all of which share the amide (peptide) chemistry with natural peptides. 

The term peptide nucleic acids was chosen because of the peptide bond in the polymer (see Sect. 5.2). The bond between the polyamide strand and the organic bases involves an acetyl group. The formation of DNA-like double helix structures by PNAs was described by Pernilla Wittung et al. (1994). The question arises as to whether peptide nucleic acids can in fact be synthesized under prebiotic conditions. 

Ladame, S. Whimey, A. Balasubramanian, S. Targeting nucleic acid secondary structures with polyamides using an optimized dynamic combinatorial approach. Angew. Chem. Int. Ed. 2005,44, 5736-5739. 

Macromolecules may be classified according to different criteria. One criterion is whether the material is natural or synthetic in origin. Cellulose, lignin, starch, silk, wool, chitin, natural rubber, polypeptides (proteins), polyesters (polyhydroxybutyrate), and nucleic acids (DNA, RNA) are examples of naturally occurring polymers while polyethylene, polystyrene, polyurethanes, or polyamides are representatives of their synthetic counterparts. When natural polymers are modified by chemical conversions (cellulose —> cellulose acetate, for example), the products are called modified natural polymers. 

The Michael addition of nucleic acid bases to dimethyl itaconate (137) has been utilized to prepare a number of condensation monomers (Scheme 39) (80MI11110). Reaction of active esters (138) with various diamines produces polyamides having the bases as pendant groups. 

In this chapter, the term oligomeric compound refers to products prepared by repeatedly linking one or several types of monomer to a growing chain of monomers. Included are biopolymers, such as peptides or oligonucleotides, and non-natural products, such as peptide nucleic acids, peptoids, or other synthetic polyamides. 

Just as the structure of a protein depends on its sequence of individual amino acids, the structure of a nucleic acid depends on its sequence of individual nucleotides. To carry the analogy further, just as a protein has a polyamide backbone with different side chains attached to it, a nucleic acid has an alternating sugar-phosphate backbone with different amine base side chains attached. 

Recently, introduction of DNA analogous detection systems such as the use of peptide nucleic acid (PNA) technology has attracted considerable attention [10]. The PNAs are synthetic analogues of DNA that hybridise with complementary DNAs or RNAs with high affinity and specificity, essentially because of an uncharged and flexible polyamide backbone. The unique physico-chemical properties of PNAs have led to the development of a variety of research and diagnostic assays where these are used as molecular hybridisation probes [11]. 

Pardridge, W.M., Boado, R.J. and Kang, Y.-S. (1995) Vector-mediated delivery of a polyamide ( peptide ) nucleic acid analogue through the blood-brain barrier in vivo. Proc. Natl. Acad. Sci. USA, 92, 5592-5596. 

The affinity towards a complementary RNA strand can be improved by using peptide nucleic acids (PNAs) [20]. These DNA mimics, in which the nucleic acid bases are linked to a polyamide backbone [21], usually exhibit improved binding properties with a complementary DNA or RNA strand [22]. The use of an excess PNA-DETA adduct 20 in a Tris-HCl buffer (pH 7), in the presence of NaCl and EDTA at 40 °C, resulted in a sequence-selective cleavage of the RNA strand 21... 

Fig. B.9.1. Molecules such as organic dyes, polycyclic aromatic compounds, organometallic complexes, saccharides, peptides, and polyamides bind to nucleic acids. Two major binding modes are possible — intercalation (left) and groove binding (right).

The life that we know also uses proteins for the majority of structural and catalytic functions. Proteins are particularly suited for these functions because of the structural properties of polymers of amino acids. The polyamide backbone of proteins is neutral, unlike that of nucleic acids. Further, the backbone has a repeating dipole able to make hydrogen bonds. These structural features are exploited as proteins fold into globular structures, as they promote the formation of stable secondary structures such as alpha helices and beta sheets. 

Peptide nucleic acids were originally developed as probes for double-stranded DNA. With a neutral polyamide backbone replacing the polyan-... 

---