Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 55

resistance to proteolytic degradation. The incorporation of dehydro amino
acids in a peptide has a pronounced rigidifying effect on the peptide back-
bone conformation. Small peptides, containing a single DPhe residue, gen-
erally adopt a b-turn structure, while helices are formed in larger peptides
[22]. This tendency is less pronounced for the E- than for the Z-configura-
tion of the double bond [23]. In contrast, DAla-containing peptides adopt
extended conformations. Several methods for the synthesis of the E- and
Z-stereoisomers have been developed, and methods for the incorporation of
these unsaturated amino acids into bioactive peptides such as enkephalin,
angiotensin, bradykinin and dermorphin have been reviewed [24].
Initially, efforts were concentrated on the development of strategies
to induce specific backbone conformations of a peptide, such as a a-helix,
b-sheet, or turn structures, by controlling the F and C angles. In this context,
cyclic peptides have played a major role in providing a global constraint of the
peptide backbone, which will be reviewed in Chapter 4. The design of
templates that mimic the secondary structures of a peptide is a field
of enormous interest. A full discussion of turn mimetics is beyond the scope
of this chapter, while helix and sheets mimics will be described in Section 3.4.
However, it has become increasingly apparent that the side-chain dihedral
angles w, in conjunction with the backbone angles, are critical for molecular
recognition and for the transduction process. The importance of the side-
chain orientation on a stable backbone template led Hruby to propose the
concept of design in w-space, or topographical design [25]. The side chain of
an amino acid can adopt three low-energy staggered conformations:
gauche( ), gauche( þ ) and anti (also termed trans ) (Figure 3.6) [25-27].
(Note that for (S)- and (R)-enantiomers of the amino acids, the orientation
of the side chain in the gauche( ) and gauche( þ ) is different [26,28].) The
orientation of the side chain relative to the peptide backbone differs greatly
between the three conformers. In the gauche( ) conformation the side chain
points to the N-terminus of the peptide, in the anti conformation it points to
the C-terminus, whereas in the gauche( þ ) conformation it is oriented per-
pendicular to the peptide backbone.

180°

+60°

H

R

H

-HN CO- CO- -HN CO-

-HN

-60°

R

H H

H R

H

H

H H

gauche(-)

gauche(+) anti

Figure 3.6 Newman projections of the three low-energy staggered conformations in
L -amino acids