Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 54

properties of the tetrahedral intermediate involved in the protease-
mediated hydrolysis of a peptide bond [15]. The stereoelectronic propor-
ties of the CF 3 group lead to a turn-like conformation, similar to the one
observed in malonyl-based retro peptides [14].
The CH(CF 3 )-NH substitution for an amide CO-NH is an example of
an amide bond replacement resulting in metabolically stabilized pseudo-
peptides. Isosteric replacements of the amide function are discussed
below. Further metabolic stabilizations can be achieved by modifications
of the peptide backbone.

R

H replace with alkyl groups

N R ′ R ′

R

H

Me O

unsaturate

N
H

N
H

N
H

R

Me

O O O

N
H

Z-didehydro amino acid E-didehydro amino acid

alkylate

O

Figure 3.5 Examples of peptide backbone modifications

The N-methylation of the amide function imparts metabolic stability and
improves membrane permeability. It also influences the peptide conforma-
tion, due to its steric hindrance and the elimination of a hydrogen bond
donor. It restricts the conformational space of the amino acid largely to
extended conformations [16,17]. Methylation of the a-carbon also results in
an increase in metabolic stability, and has a strong effect on the conforma-
tion of the peptide. a,a-disubstituted amino acids (or C a -tetrasubstituted
a-amino acids) are very effective in inducing secondary structure, in parti-
cular helical structure. A prominent example is the achiral Aib (a-aminoi-
sobutyric acid) residue, which is a strong helix inducer [18]. However, other
a,a-disubstituted amino acid analogues such as the carbocyclic Ac n cseries
have also been used for their helix-inducing properties. In contrast,
C a -ethylated residues, or achiral residues with two identical side chains
longer than a methyl group, have been shown to induce fully-extended
conformations [19]. In small peptides, C a -methylated amino acids such as
a-MePro induce turn structures [20]. Because of the steric hindrance of the
a,a-disubstituted amino acids, their synthesis requires appropriate coupling
conditions [21]. In a,b-didehydro-a-amino acids (DAaa), the chirality at
the a-carbon is removed, while the orientation of the side chain is fixed in
the E- or Z-geometric isomers (Figure 3.5). These unsaturated amino acids
are components of many naturally occurring linear and cyclic peptides of
microbial, plant and animal origin. Didehydropeptides have an increased