Biomedical Engineering Reference
In-Depth Information
In linear peptides, the retroinverso principle has been exploited to design
modified peptides. Such a retroinverso peptide has a similar side-chain
topology as the parent peptide, but the end groups are noncomplimentary,
which can result in inactive compounds (Figure 3.4). This problem can be
solved by incorporating a
gem
-diaminoalkyl residue at the amino terminus
and a C2-substituted malonyl residue at the C-terminus [7]. The incorpora-
tion of these diaminoalkyl and malonyl residues within the peptide
sequence results in partially modified retroinverso (PMRI) peptides. The
intervening amino acids have an inverted configuration, while the end
groups are identical to those in the parent peptide. Extensive reviews of
the synthetic methods [4,9] and biological applications [7,9] have been
published. A critical review [12] claims that the retroinverso strategy has
been especially successful in immunological applications, where the partial
retroinversion is more promising since crucial hydrogen bonding through
the peptide bonds can be maintained, while still obtaining a metabolic
stabilization of the crucial peptide bonds. As an alternative to the config-
urationally unstable malonyl residue, the [NH-CH(CF
3
)]Gly modification
has been developed for application in partially modified retro peptides
[13-15] (Figure 3.4). In this unit, a carbonyl CO is replaced by a CH(CF
3
).
The resulting NH-CH(CF
3
) group closely resembles the NH-CO bond,
since the C-CF
3
bond is isopolar with the C
¼
O, the NH has a low basicity
and the o backbone angle is close to 120. It also, however, has some of the
R
2
R
4
O
O
H
N
H
2
N
OH
N
H
N
H
R
1
R
3
O
O
peptide
R
2
R
4
R
2
O
R
4
O
O
H
N
H
N
H
N
H
N
H
2
N
OH
HO
H
NH
2
H
R
1
R
3
R
1
R
3
O
O
O
O
O
retroinverso peptide(all-D peptide)
end-group modified retroinverso peptide
O
R
2
O
R
4
O
O
Bn
CF
3
O
H
N
H
2
N
OH
OBn
H
H
H
MeO
N
H
N
H
R
1
R
3
R
1
O
O
O
gem-diaminoalkyl
2-alkyl-malonyl
PMRI
Ψ
[NHCH(CF
3
)]Gly peptide
partial retroinverso peptide(PMRI)
Figure 3.4 The principle of partially modified retroinverso (PMRI) peptides
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