O

peptoid peptide nucleic acid

Fig. 8.1 Chemical structures of various residues for a-peptide, b-peptide, peptoid, and peptide nucleic acids (PNA).

native deprotection protocols [59, 60] and increased deprotection temperatures [37]. Nonetheless, b-peptide libraries have been synthesized and screened by combinatorial methods [43, 44].

b-Peptides exhibit significant metabolic stability under in vivo conditions [61, 62]. b-Peptides subjected to various robust peptidases (i.e. proteinase K) remained intact after 48 h, whereas analogous a-peptides were completely degraded within 15 min [62]. The pharmacokinetics of b-peptides are equally impressive, with elimination half lives of 3-10 h, compared with less than 15 min for analogous a-peptides following intravenous injection in rats [62]. b-Peptides can also cross cell membranes and localize to the cell nuclei by the appendage of b-peptide segments derived from HIV-1 Tat proteins [28]. This permits the design of b-peptides that can affect biological targets in the nucleus.

8.1.2 Peptoids

Peptoids are oligomeric peptidomimetics composed of N-substituted glycines (see Chapter 1) [12-15]. Compared with natural a-peptides, peptoids differ by the appendage of side chains to the amide nitrogen atoms of a peptide backbone, rather than to the a-carbons for natural a-peptides (Fig. 8.1). Peptoids as short as five residues bearing certain bulky a-chiral aromatic or aliphatic side chains can adopt a stable helical structure similar to the type-I polyproline helix, with cis-amide bonds, three residues per turn, and 6.0 A pitch (see Section 1.4.2 in Chapter 1) [12-15, 63-68].

Peptoids are readily synthesized by solid phase techniques [69] and are amenable to combinatorial methods [70, 71]. Unlike other foldamer types, peptoids are prepared by submonomer synthesis [69]. Peptoid synthesis is an iterative two-step process of bromoacetylation of the N-terminal secondary amine followed by Sn2 displacement of the bromide by side chain bearing amines [69]. Synthesis therefore proceeds without the need for producing suitable quantities of a diverse set of protected monomers as in solid phase peptide synthesis. Peptoids exhibit poor oral absorption, as only 3-8% of orally administered peptoids were absorbed in rats [72]. Nevertheless, peptoids have been shown to be stable against multiple proteases in vitro [73, 74]. Furthermore, peptoids introduced intravenously into rats were eliminated primarily in the feces without degradation [72], while an a-peptide tetramer was completely metabolized in the blood within 2 h.

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