Peptides, amino acid mimics

Figure 3.1 Peptidomimetic chemistry attempts to produce a non-peptidic drug to mimic a bioactive peptide. In Step A, the smallest bioactive fragment of the larger peptide is identified in Step B, a process such as an alanine scan is used to identify which of the amino acids are important for bioactivity in Step C, individual amino acids have their configuration changed from the naturally occurring L-configuration to the unnatural D-configuration (in an attempt to make the peptide less naturally peptidic ) in Step D, individual amino acids are replaced with atypical unnatural amino acids and amino acid mimics in Step E the peptide is cychzed to constrain it con-formationally finally, in Step F, fragments of the cyclic peptide are replaced with bioisosteres in an attempt to make a non-peptidic organic molecule.

It is well established that control of peptide conformation allows the tertiary structure vital for enzyme activity. Unnatural a and p amino acids are particularly useful in this regard for designing peptides with controlled conformation and thus targeted function, but amino add mimics have also been put to good effect in this regard. This was the goal of Pannecoucke when he successfully synthesized en antiopure monofluorinated allylic amines as site spedfic amino acid mimics in peptides (Scheme 7.12) [38]. 

Insulin and Amylin. Insulin is a member of a family of related peptides, the insulin-like growth factors (IGFs), including IGF-I and IGF-II (60) and amylin (75), a 37-amino acid peptide that mimics the secretory pattern of insulin. Amylin is deficient ia type 1 diabetes meUitus but is elevated ia hyperinsulinemic states such as insulin resistance, mild glucose iatolerance, and hypertension (33). Insulin is synthesized ia pancreatic P cells from proinsulin, giving rise to the two peptide chains, 4. and B, of the insulin molecule. IGF-I and IGF-II have stmctures that are homologous to that of proinsulin (see INSULIN AND OTHER ANTIDIABETIC DRUGS). 

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. 

The field of synthetic enzyme models encompasses attempts to prepare enzymelike functional macromolecules by chemical synthesis [30]. One particularly relevant approach to such enzyme mimics concerns dendrimers, which are treelike synthetic macromolecules with a globular shape similar to a folded protein, and useful in a range of applications including catalysis [31]. Peptide dendrimers, which, like proteins, are composed of amino acids, are particularly well suited as mimics for proteins and enzymes [32]. These dendrimers can be prepared using combinatorial chemistry methods on solid support [33], similar to those used in the context of catalyst and ligand discovery programs in chemistry [34]. Peptide dendrimers used multivalency effects at the dendrimer surface to trigger cooperativity between amino acids, as has been observed in various esterase enzyme models [35]. 

Covalent binding of peptides to polymer surfaces is now a standard method to improve their biocompatibility. The primary amino acid sequence of a peptide can be chosen to mimic the putative... 

In an attempt to design the p-turn-peptide-mimics, aspartic acid (an amino acid also known as aspartate) and lysine (an amino acid especially found in gelatin and casein) were attached to each amine group of 1,3-diaminoada-mantane in the form of amide bonds. The term p-turn refers to a peptide chain that forms a tight loop such that the carbonyl oxygen of one residue is hydrogen... 

Figure 7.2 Schematic showing the relationship of the native antigen to the peptide mimic. The native antigen (a protein) is shown as a winding, twisted line, so as to represent a hypothetical three-dimensional structure. The peptide represents the antibody-binding epitope (shown in dotted lines) of the native antigen. The epitope can represent a linear sequence of the native protein. Alternatively, the epitope can be formed by amino acids that are not immediately adjacent to each other in the primary sequence but brought together by the three-dimensional folding of the protein. Adapted with permission from Sompuram et al.6...

Both proteinaceous and non-proteinaceous analogs have been studied. Examples include a synthetic 20 amino acid adhesin peptide sequence copied from S. mutans and LTA of groups A and B streptococci. The synthetic peptide mimics a S. mutans adhesin that binds a salivary protein on dental surfaces and was shovm to inhibit bacterial adherence to immobilized salivary receptors in vitro. In vivo, this peptide hindered the recolonization by S. mutans on teeth that had been cleared of the... 

Peptide Vaccines Peptide vaccines are chemically synthesized and normally consist of 8-24 amino acids. In comparison with protein molecules, peptide vaccines are relatively small. They are also known as peptidomimetic vaccines, as they mimic the epitopes. Complex structures of cyclic components, branched chains, or other configurations can be built into the peptide chain. In this way, they possess conformations similar to the epitopes and can be recognized by immune cells. An in silico vaccine design approach has been used to find potential epitopes. A critical aspect of peptide vaccines is to produce 3D structures similar to the native epitopes of the pathogen. 

Using the knowledge that rabies virus can spread into the brain neurons, scientists mimic its delivery system. A short, 29 amino acid peptide chain is derived from the rabies virus glycoprotein (RVG). The RVG binds to the acetylcholine receptor on the neurons and the endothelium cells of the blood-brain barrier. Through this interaction, transvascular delivery is enabled. 

A synthetic peptide has been designed to mimic the effects of viral fusogenic properties (114,115). It consists of 30 amino acids with the major repeat of Glu-Ala-Leu-Ala so, it is referred to as a GALA peptide. It undergoes a conversion from an aperiodic conformation at neutral pH and becomes an amphipathic alpha helix at pH 5. In the more acidic environment, the peptide interacts with lipid bilayers (114,115). GALA has been incorporated into transferrin-targeted liposome, with the effect of significantly... 

While functional (immunological) mimicry has been established, the basis of mimicry on the molecular level remains to be explained. Several hypotheses have been put forward one of the earliest was that the side chains of aromatic amino acid residues might mimic the hydrophobic faces of the pyranosyl rings of carbohydrates. Before 1997, no structural evidence was available to support or discount these hypotheses. The nature of peptide-carbohydrate mimicry on the molecular level became the subject of structural investigations, and the resulting studies along with functional data will be discussed below. 

A thiazolium amino acid (Taz) has been developed which can be utilized to mimic TDP-dependent enzyme function [52]. In this strategy, illustrated in Fig. 15, the commercially available amino acid 4-thiazolylalanine is incorporated into peptides by solid phase peptide synthesis. Prior to deprotection of the amino acid side chains and cleavage of the peptide from the resin, the thiazole amino acid is alkylated with an alkyl halide to generate the corresponding thiazolium amino acid having various N3-substituents (BzTaz = 3-benzyl-Taz, NBTaz = 3-nitrobenzyl-Taz). 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

This review will focus on the use of MCR approaches to cyclic peptides, cyclic peptidomimetics, or cyclic pseudopeptides, including small or medium-sized heterocycles as mimics of peptide motifs and macrocycles with amino acid or peptide moieties. 

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