Amino acids, conformationally cyclic peptides

The effect of C ,C -disubstituted amino acids (aaAAs) on peptide secondary structure has been studied in recent years.2a d While longer side-chain C ,C -di-n-alkyl amino acids promote extended peptide conformation,23 alicyclic aaAAs, in which the Ca carbon forms a cyclic bridge with itself, such a 1-aminocyclopentane-l-carboxylic acid (Ac5c) and 1-aminocyclohexane-l-carboxylic acid (Ac6c), have helix-forming characteristics similar to those of 1 -aminoisobutyric acid (Aib).2ax... 

Conformational restriction can be introduced into flexible peptides by a variety of methods. For example, Marshall et al. introduced a-methyl amino acid substituents into peptides as a way to decrease the conformational space available to the resulting peptide. Freidinger et al. developed a cyclic lactam moiety (23.31) that stabilized p- and y-tum structures and applied this to LH-RH (e.g. (23.32)) to show that a p-tura about residues 6-7 was compatible with activity." Conformational restriction has been applied to determine the bioactive conformation of enzyme-inhibitor systems for which no X-ray crystal structure is available. Thorsett" synthesized conformationally restricted bicyclic lactam derivatives of the angiotensin-converting enzyme (ACE) inhibitors enalapril (2333) and enalaprilat (23.34) (Fig. 23.6) in order to characterize torsion angles in the bioactive conformation. Analog (23.35) was used to constrain... 

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. 

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." ... 

Cyclic peptides are important biologically active compounds that combine peptide properties with conformational bias and often improved serum stability and membrane penetration [1-3]. Depsipeptides are similar compounds, but they contain as part of their backbone one or more hydroxylated amino acid residues that add ester or lactone moieties to the peptide (Fig. 1) [4-6]. Cyclo- and... 

The important difference between linear and cyclic peptides is the reduced conformational flexibility imposed by the cyclization. 14,151 Cyclic peptides have, therefore, been under intense investigation with respect to their conformational preferences 30,31 and their different turn motifs, e.g. reverse turns. 32 35 To differentiate between the structural influences of the numerous sequence elements the following special concepts have been described 161 (1) Global constraints are structural characteristics that restrict the whole molecule, e.g. the macrocyclic structure of the peptide framework and (2) local constraints comprise a large number of structure-inducing building blocks, such as proline, D-amino acids, and turn mimetics. 

Most, if not all of the larger size natural cyclic peptides contain one or more N-alkylated amino acid residue. Their ring conformation depends on the substitution patterns as well as on environmental conditions (crystal, solvent). As a result of the large number of energetically similar and thus allowed conformational states, their 3D structure can not be predicted with great certainty. 

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