Peptide backbone mimetics

Enantiopure N,N -hnked oligoureas were originally described in 1995 by Burgess and coworkers as novel peptide backbone mimetics [271, 272]. Several synthetic approaches have been reported, all of which involve sequential acylation and amine deprotection cycles using appropriately protected carbonyl synthons [83, 271, 272, 274, 286-288]. Although elongation can be performed in solution, most of the synthetic procedures are elaborated on solid supports starting from Rink s... 

Based on these considerations, four distinct types of peptidomimeticshave been identified to date (9,10). The first invented were structures that contain one or more mimics of the local topography about an amide bond (amide bond isosteres). Strictly speaking, these are properly classified aspseudopeptides (11), but in recent years, they have been called peptidomimetics on occasion. For historical reasons, we classify the peptide backbone mimetics as type I mimetics (Table 15.1). These... 

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

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

Conformationally restricted mimetics of reverse turns limit the potential array of conformations adopted by the peptide backbone and thus allow one to potentially validate the presence of reverse-turn pharmacophores. Therefore, there is significant interest in the design and synthesis of y-turn inducers and mimetics. 

Cyclic peptides are of interest as turn mimetics or as conformationally constrained peptide analogs. The cyclization of peptides can either be performed after cleavage from the support in solution (see, e.g. [58]) or while still on the support. Besides cycli-zations of the peptide backbone, peptides can be cyclized through their side chains or by means of a non-natural spacer. To cyclize the backbone of a peptide on an insoluble support, the peptide must be attached to the support either by a backbone amide linker [59] or via the side chain of an amino acid [60] (Figure 16.7). 

Work by Stefan Matile in Geneva, Switzerland, has resulted in a number of interesting [i barrel mimetic anion transporting pores such as 12.38 (Figure 12.17).27 A [5 barrel is a kind of natural protein that forms a rigid channel by self-assembly of peptides into a /3-sheet type of secondary structure. The peptide backbone is mimicked by the rigid octaphenyl backbone which is ca. 3.4 nm long and hence spans... 

While this monocyclic reverse-turn template clearly mimics the backbone conformation and side-chain presentations of p- and "y-tums quite well, one concern with such a large macrocycle is that the relatively flexible peptide backbone conformations are strongly influenced by the side-chain-side-chain interactions, as investigated by NMR solution structure (Fig. 29.11). ° We therefore needed a new type of turn mimetic bearing a constrained and rigid skeleton which could potentially enhance binding and/or improve bioavailability. Based on the conformational analyses of several heterobicyclic systems, we envisioned... 

Peptidic p-tum mimetics are generally based on cyclic backbone mimetics (e.g. replacing the turn hydrogen bond by a covalent bond) or by introducing one or several unusual amino acids, which constrain the backbone in P-tum conformations. Synthetic approaches to non-peptidic turn mimetics can be grouped into two classes 1) external P-turn mimetics, and 2) internal P-turn mimetics. ... 

Use of D-amino acids in the synthesis of a hairpin loop portion from the CD4 receptor provides a stable CD4 receptor mimic, which blocks experimental allergic encephalomyelitis (144). This synthetic constmct is not simply the mirror image or enantiomer of the CD4 hairpin loop, but rather an aH-D-constmct in the reverse sequence, thus providing stereochemicaHy similar side-chain projections of the now inverted backbone (Fig. 11). This peptide mimetic, unlike its aH-L amino acid counterpart, is resistant to en2yme degradation. As one would expect, the aH-D amino acid CD4 hairpin loop, synthesi2ed in the natural direction, the enantiomer of the natural constmct, is inactive. 

While the a-helix of L-a-peptides and the (M)-3i4 helix of the corresponding peptides have opposite polarity and helicity (see Section 2.2.3.1), the inserhon of two CH2 groups in the backbone of L-a-amino acids leave these two hehx parameters unchanged, both the a-helix and the 2.614-hehx of the resulting y" -peptides being right-handed and polarized from N to C terminus. In view of these similarities, the y-peptide hehcal fold might prove useful as a template to elaborate functional mimetics of bioachve a-polypeptides. 

Although biologically active helical y-peptides have not been reported so far, the striking structural similarities (polarity and helicity) between the a-helix of L-a-peptides and the (P)-2.6i4-hehx of y-peptides suggest that the 2.614-helical backbone might prove useful as a template for elaborating functional mimetics of a-helical surfaces and intervening in protein-protein interactions. 

Substmcture search of this backbone (smiles O = C(N(C)C1C)CN(C)C1=0) reveals several hundreds commercially available compounds, which likely have been synthesized by the above synthetic route [1]. This backbone can also be considered as a peptide mimetic by using a-amino acid derived isocyanide and amine components and will be of value for biological studies and for the discovery of hydrolysis resistant and biologically active peptide fragments (Fig. 6). 

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