Amino acid mimetics

Stancovic CJ, Plummer MS, Sawyer TK (1997) Peptidomimetic ligands for src homology-2 domains. In Abell A (ed) Advances in amino acid mimetics and peptidomimetics. Jai Press, Greenwich, vol 1, p 127... 

F.A. Etzkorn, J.M. Travins, S.A. Hart, Rare protein turns y-turn, helix-turn-helix, and cis-proline mimics, Adv. Amino Acid Mimet. Peptidomimet. 2 (1999) 125-163. 

Abell A. Advances in Amino Acid Mimetics and Peptidomimetics, Vol. 2. 1999. JAI Press Inc., Stamford, CT. 

Amino add transporters seem to hold a great potential for intestinal absorption of drugs and drug candidates. However, overall, the information on the impact of these transporters in terms of mediating oral bioavailability of amino acid mimetics is rather limited, and systematic investigations using both in vitro and in vivo data are highly antidpated. 

Bannwarth L, Kessler A, Pethe S et al (2006) Molecular tongs containing amino acid mimetic fragments new inhibitors of wild-type and mutated HIV-1 protease dimerization. J Med... 

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. 

The importance of proper immobilization of enzymes can be shown in the kinetic resolution of racemic a-acetoxyamides. This group of compounds is an important class of chemicals since they can be readily transformed into a-amino acids [17], N-methylated amino acids, and tripeptide mimetics [18], amino alcohols [19], 1,2-diols [20], 1,2-diamines [21], and enantiopure l,4-dihydro-4-phenyl isoquinolinones [22]. 

Capping Croups as Amino Acid Analogues and Dipeptide Mimetics... 

Other potent peptide mimetic NS3 protease inhibitors have been reported that incorporate a serine trap on the C-terminal end of the peptide. Thus, the inhibitory activity of telaprevir (VX-950, 59), (7nM vs. NS3, 300 nM vs. the la replicon) is based on truncation of the polypeptide substrate, maximizing binding by alteration of amino acids at the scissile site, and capping both N- and C-terminal ends, the latter with a known dicarbonyl serine trap. This compound has exhibited impressive antiviral activity in animals, and showed a 4.4 log drop in viral load in genotype 1-infected patients in a Phase lb clinical trial [110]. Telaprevir is expected to enter Phase 3 clinical trials in 2007. Additional bicyclo-proline-based P2 tetrapeptides, represented by analog 60 (Kj = 22 nM), have been explored. Although the compounds are selective inhibitors of NS3, little or no cell-based replicon activity was reported, presumably due to poor cellular permeability [111-114], A diastereomer of telaprevir, has been reported to inhibit the replicon with an EC50 of 0.55 pM [115]. 

Recent research deals with stereoselective 1,3-dipolar cycloadditions of nitrones for the syntheses of alkaloids and aza heterocycles asymmetric synthesis of biologically active compounds such as glycosidase inhibitors, sugar mimetics, /3-lactams, and amino acids synthesis of peptido-mimetics and peptides chemistry of spirocyclopropane heterocycles synthesis of organic materials for molecular recognition and photochemical applications. 

Much of the recent work on the use of anodic amide oxidation reactions has focused on the utility of these reactions for functionalizing amino acids and for synthesizing peptide mimetics [13]. For example, in work related to the cyclization strategy outlined in Scheme 3, the anodic amide oxidation reaction has been used to construct a pair of angiotensin-converting enzyme inhibitors [14]. The retrosynthetic analysis for this route is outlined in Scheme 4. In this work, the anodic oxidation reaction was used to functionalize either a proline or a pipercolic add derivative and then the resulting methoxylated amide used to construct the bicyclic core of the desired inhibitor. A similar approach has recently been utilized to construct 6,5-bicyclic lactam building blocks for... 

Macrocyclization of esters of allylglycine with diols has been successfully used to prepare derivatives of 2,7-diaminosuberic acid [861,864]. The latter are surrogates of cystine, and therefore of interest for the preparation of peptide mimetics. For unknown reasons protected allylglycine derivatives can not be directly dimerized by self metathesis [864]. However, catechol [864], ethylene glycol [861], and 1,2- or 1,3-di(hydroxymethyl)benzene derivatives [860] of allylglycine are suitable templates for the formal self metathesis of this amino acid via RCM. 

Figures Selective protein modification using a keto amino acid, p-acetyl-L-phenylalanine. (a) Labeling of fluorescein hydrazide to the Z domain protein. Only the mutant protein containing p-acetyl-L-phenylalanine was labeled and became fluorescent, (b) A general method for preparing glycoprotein mimetics with defined glycan structure.

The binding affinity of carbohydrate-mimetic peptides can be quite high, often higher than the natural carbohydrate ligand. Carbohydrate-mimetic peptides do not share any general chemical features, and all amino acid residues are represented there is no evidence for an unusual importance of aromatic residues in mimicry. In several cases, o-amino acids have been incorporated, and unusual amino acids (derived from nonribosomal peptide synthesis) have been found in naturally occurring carbohydrate-mimetic peptides. 

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