Peptidomimetics approaches

Phosphonopeptides containing a transition state analog of the hydrolysis of the amide bond represent another attractive approach for the preparation of proteolitically stable peptides (10,30,31). In addition to increased stability, incorporation of a phosphonate moiety into the peptide sequence provides access to additional binding interactions within the transition-state conformation of the enzyme/substrate complex (13). This peptidomimetic approach is used to design very effective protease inhibitors (31-34). As in the case... 

Peptidomimetic approaches are heavily used to build protease inhibitor scaffolds. Selective protease inhibitors are quite straightforward to be obtained because of the substrate variety and specificity of the proteases. However, the concept of privileged scaffolds does not carry far for proteases. The unifying element in protease substrates is the extended beta-strand conformation that allows interactions with four to six subpockets in the protease active site (69). Mimics for this conformation have been developed but they still lack universal applicability for the transfer into clinical application (70). 

In this sedion, we will review the anticancer activity of some cationic, amphipathic peptides which have historically been known as AMPs but whose nomendature is evolving toward HDPs due to their multiple roles, as well as proposed mechanisms of their anticancer actions. Furthermore, strategies like peptidomimetic approaches and selective delivery methods that can improve the efficacy of this new dass of compounds will also be discussed. 

Of particular interest in medicinal chemistry is the inclusion of non-standard amino acids in therapeutic peptides or peptidomimetics [15] to overcome these problems. Peptidomimetic approaches employing p-amino acids (Figure 14.2) have shown potential in recent years since P-amino acids are similar enough to their a-analogs to function as required while reducing the rate of peptide hydrolysis by proteases and consequently improving the pharmacokinetic properties of these compounds [16]. 

A similar approach has been described by the same authors for the synthesis of related cyclic peptidomimetics [44]. A set often nucleophiles was employed for the substitution of the chlorine atom of the cyclic triazinyl-peptide bound to the cellulose membrane. By virtue of the aforementioned rate enhancement effects for nucleophilic substitution of the solid-supported monochlorotriazines, these reactions could be rapidly carried out by microwave heating. All products were obtained in high purity, enabling systematic modification of the molecular properties of the cyclic peptidomimetics. 

These examples clearly prove the viability of a structure-based peptidomimetic design approach for developing non-peptide peptidomimetics for therapeutic interference into protein-protein interaction events. 

The most common bicyclic 5-6 system with one bridgehead N-O and one extra heteroatom described in the period covered in this chapter has been the diketopiperazine derived from proline as it is present in natural products, in biologically active synthetic molecules, and has been used as starting material for the preparation of conformationally constrained peptidomimetics. The classical approach to this class of molecule is the ring closing of the dipeptide derived from proline and another amino acid via nucleophilic attack of the NH2 to the activated carboxylic group. This method has been applied several times to prepare different diketopiperazines for different uses. 

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. 

The use of an anodic amide oxidation to introduce a vinyl group to the C5 position of a proline derivative has proven to be an effective strategy for building other constrained peptidomimetics as well. For example, a variation on the approach has... 

Fig. 27 Application of 3-isocyano dihydropyridones (85) in the multicomponent approaches toward conformationally constrained depsipeptides (86), dihydrooxazolopyridmes (87), and conformationally constrained peptidomimetics (88)...

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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