Carbohydrates in Peptide and Protein Design - Peptide and Protein Design for Biopharmaceutical Applications - page 180

the main problems with peptides as drug candidates are their poor
bioavailability and their lability to proteolysis. Cyclization is an
approach to overcoming the latter, as it can improve metabolic stability
(see Chapter 4).
The conformation of the peptide backbone can be described by three
torsional angles: f (phi), which at 180 implies that the two carbonyls are
trans ; c (psi), which at 180 implies that the two amides are trans ; and o
(omega), which at 180 indicates that the amide bond has a trans orienta-
tion [6]. Since the amide bonds of the peptide units are relatively rigid
groups - with restricted rotation around the C(O)-N amide bond - that
are linked into a chain by covalent bonds at the C a atoms, the only
degrees of freedom they normally have are rotations around two bonds
(angle of rotation around N-C a is f and angle of rotation around
C a -C(O) is c) (Figure 5.2). However, most combinations of f and c
angles are not allowed because of steric collisions between the side chains
and the main chains; Ramachandran plots give combinations of experi-
mental f and c angles in a diagram.
Incorporation of carbohydrate structures into peptides, i.e. the use
of carbohydrates in peptide design, generates new nonpeptide pepti-
domimetic structures. Structural elements in peptides include
a-helices, parallel and antiparallel b-sheets, other types of helices and
a-, b-andg-turns. Of these structures, carbohydrates can readily be
envisioned as mimetics of turn motifs, based on their pseudocyclic
structure with (pseudo)axial and (pseudo)equatorial orientation of
substituents. Turns (see also Chapters 3 and 4) in peptides consisting
of a-amino acids are classified by the number of residues in the regular
structure: b-turns, four amino acids; g-turns, three amino acids [8].
Turns are stabilized, or constrained, by a hydrogen bond across them,
holding the two ends together. The first residue is defined as i ;in
idealized b-turns, the hydrogen bond is between the carbonyl of the i
residue and the NH of the i þ 3 residue, forming a 10-membered ring
[9]. In g-turns the hydrogen bond is between the carbonyl of the i
residue and the NH of the i þ 2, forming a 7-membered ring. Classical
types of b-turns include I, I 0 , II, II 0 b-turns, characterized by different
angles. b-turns are generally located at the surfaces of proteins,
are hydrophilic with potentially reactive functional groups, and are
often recognition sites [8]. Thus, a b-turn mimetic that often repre-
sents an appealing drug target would require control of four separate
asymmetric centres [8].
This chapter focuses on structural aspects of carbohydrates in peptide
design. In most cases the carbohydrate will function as a scaffold, i.e. as a