Biomedical Engineering Reference
In-Depth Information
3.4.2.1
Helix nucleators
As for the b-sheet nucleators, templates have been designed in which the
orientation of the NH or CO groups is fixed in a rigid structure in order to
initiate helix formation [291] (Figure 3.40).
The Kemp group was the first to propose a helix scaffold that positions
three carbonyl groups in an orientation that allows them to form hydro-
gen bonds with the amide NH protons of the attached peptide, thereby
inducing a distorted a-helix [292].
Satterthwaith introduced the concept of a hydrogen-bond surrogate
(HBS) in his template, which mimics one turn of an a-helix, and uses a
hydrazone-ethylene bridge as a covalent replacement of the hydrogen
bond [293]. A solid-phase procedure to assemble this helix nucleator
has been developed [294] and was applied to the development of a
restricted peptide derived from the human papillomavirus that was recog-
nized by sera from women having cervical carcinoma [295]. This concept
was recently further developed by using an allyl group as the HBS. This
helix-nucleator can be very conveniently prepared by metathesis reaction
of a bis-allyl precursor [296-298] and induces a-helix formation in short
peptides, as confirmed by X-ray crystallography [299-301]. A con-
strained Bak BH3 peptide sequence was shown to bind to the Bcl-xL
protein and to be resistant to trypsin cleavage [302]. An HBS-based
artificial helix inhibited the gp41-mediated HIV-1 fusion [303].
O
R
i+4
O
O
N
CH
3
H
N
N
H
O
O
R
i+3
O
H
N
O
R
i+2
O
R
HN
O
N
N
N
N
H
O
O
N
O
HN
H
O
O
N
HN
O
N
R
i
O
H
N
N
O
R
i+1
HN
N
s
CH
3
Satterthwait HBS template
Kemp template
s
O
O
O
R
O
N
N
H
O
N
O
R
O
R
H
O
N
Cbz-HN
H
3
C
R
R
N
R
N
HN
H
H
3
C
O
HN
H
O
O
COOH
NH-Boc
O
N
H
H
H
3
C
OH
CH
3
CH
3
R
N
H
O
allyl-based HBS template
Bartlett template
Bartlett template
CH
3
Figure 3.40 Helix-inducing templates
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