Peptides pseudopeptide backbone

Nielsen P.E., Haaima G. Peptide nucleic acid (PNA). A DNA mimic with a pseudopeptide backbone. Chem. Soc. Rev. 

Peptide nucleic acids (PNAs) are a class of polymers with peptide or pseudopeptide backbones and pendant nucleotide bases. PNAs typically lack the helicity of DNA but benefit from stronger association and solubUity in organic... 

Peptide nucleic acid (PNA) probes as a DNA analogue that possess an uncharged pseudopeptide backbone instead of the charged phosphate-sugar backbone of natural DNA and, consequently, greater affinity to complementary DNA and better distinction between closely related sequences [33]. 

The synthesis of phosphinic peptides by a reverse sequence of P-C bond formation events (N+PC approach) is a less frequently applied strategy which may offer important diversification possibilities. In particular, an amidoalkylation condensation reaction between amides, aldehydes, and alkylphosphinic acids (the three-component Kabachnik-Fields reaction) affords in a single step the main pseudopeptidic backbone, thus facilitating fast screening of the nature of Pi position. In 1996, Chen and Coward observed that a mixture of benzyl carbamates, aldehydes, and alkylphosphinic acid 23 in AcCl can lead to Cbz-protected phosphinic pseudodipeptides 24 (Scheme 10a) [53]. This method was adjusted by Matziari et al. to the synthesis of Fmoc-protected phosphinic building blocks 25 and peptides thereof (Scheme 10b) [54]. 

Peptide nucleic acids (PNA Fig. 10) are synthetic polynu-cleobase molecules which bind to DNA and RNA with high affinity and specificity. PNA was constructed with a charge-neutral, achiral, pseudopeptide backbone and is therefore chemically more closely related to peptides than to nucleic acids. Thus, PNAs, because of their backbone properties, show extremely good nucleic acid hybridization properties. In fact, PNA-DNA and PNA-RNA duplexes are, in general, thermally more stable than the corresponding DNA(RNA)-DNA(RNA) duplexes. 

Two successful attempts have been reported to replace the entire deoxyribose phosphate backbone on one side and still preserve the features of the DNA structure especially in view of antisense and antigene potential on the other side [85,86,87,88,89,90], One is the morpholino derivative and the other one the peptide nucleic acids (PNA) which contains an N-(2-aminoethyl) glycine-based pseudopeptide backbone (Figure 8) [71], It is obvious from the way PNA can mimic DNA that the deoxyribose backbone is not essential for the function of a helical duplex structure. 

The dimethoxybenzyl group was used for backbone protection of the pseudopeptides of the form Xaai/r(CH2N)Gly (Xaa = amino acid). It is introduced by reductive alkylation with the aldehyde and NaCNBH3. Acidolysis with TFMSA in TFA/thioanisole is used to remove it from the amine, but the efficiency is dependent upon the peptide sequence. ... 

Pseudopeptides are not always clearly defined in the literature. Here, we use the term to mean compounds with a modified peptide backbone, namely with some or all peptide bonds replaced by bioisosteric surrogates. 

As stated above, we define pseudopeptides as compounds having a modified peptide backbone, namely with at least one peptide bond replaced by a bioisosteric surrogate (summarized in Table 6.7) [139][181][234], Such surrogate groups are nonhydrolyzable by nature, or hydrolyzable only under severe conditions in the case of the S02-NH bond. In the vast majority of published pseudopeptides, only one or a very few peptide bonds had been replaced and most monomeric units are amino acids, meaning that such pseudopeptides do qualify as peptides. 

Vinylogous sulfonamide peptides may be considered as pseudopeptides, dipeptide mimetics, or pseudopeptides with five atoms in the backbone, instead of the usual six atoms in pro-teinogenic dipeptides (Scheme 31). 

Modification of the peptide backbone, including C -alkyl a-amino acids, a, 3-didehydro a-amino acids, and Na<->C and C° Ca cyclized a-amino acids and dipeptides, may influence the conformational properties of the resulting pseudopeptide molecules while preserving the mandatory side-chain substituents. 

Fig. B.19.1. Peptide nucleic acid (PNA) is a DNA analog in which the (deoxy)ribosephosphate backbone has been replaced by an artificial pseudopeptide.

Most synthetic DNA analogs represent logical departures from the natural structure. However, one of the most radical structural modifications of DNA to appear in the literature is peptide nucleic acid (PNA, Fig. 1), in which the sugar-phosphate backbone is abolished entirely in favor of a pseudopeptide. PNA was first reported by Nielsen et al. in 1991... 

Type I Peptide backbone mimetics Substrate-based design Pseudopeptides... 

The replacement of amide bonds by retro-in-verso amide replacements (71, 72) and other amide bond isosteres generates pseudopeptides (11). This process was first used to stabilize peptide hormones in vivo and later to prepare transition state analog (TSA) inhibitors. Systematic efforts to convert good in vitro inhibitors into good in vivo inhibitors became the driving force for further development of peptidomimetics. Figure 15.17 illustrates some of the peptide backbone modifications that have been made in an effort to increase bioavailability. Replacement of scissile amide (CONH) bonds with groups insensitive to hydrolysis (e.g., CHaNH) has been extensively practiced. Reviews of this work have appeared (11,73). Removal of the proton donors and... 

Figure 15.17. Isosteres that replace peptide backbone amide groups to generate pseudopeptides.

Solid-Phase Synthesis of Pseudopeptides and Oligomeric Peptide Backbone Mimetics... 

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