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and enforce b-peptide secondary structure towards the generation of artificial b-peptidic
zinc fingers, a mimic of a natural motif found in proteins [45]. To this aim, a b-decapep-
tide, four b-octapeptides and a b-hexadecapeptide were designed and synthesized. For the
first five b-peptides, the design was such that the peptides would: (i) fold to a 14 -helix (a
helical secondary structure defined by 14-membered ring hydrogen bonds [43c]), a hair-
pin turn or neither and (ii) incorporate the cysteine and histidine side chains in strategic
positions to allow the binding of Zn in order to stabilize or destabilize the intrinsic
secondary structure of the peptide. The b-hexadecapeptide was designed to: (i) fold into a
turn to which a 14 -helix is attached through a b-dipeptide spacer and (ii) contain two
cysteine and two histidine side chains for Zn complexation in order to mimic a Zn fin-
ger motif. b-Peptides were generated by manual solid phase synthesis [46]. After cleav-
age from the resin, the b-peptides were purified by preparative HPLC and characterized
by analytical HPLC, MS, NMR and CD measurements. Dramatic changes of the CD pat-
tern take place when ZnCl 2 is added to aqueous solutions of the b-peptides, buffered at
pH
6.04). Although the CD spectra demonstrate that there are
interactions between the b-peptides and Zn ions in solution, they do not provide any
structural information for further qualitative assignments. Some CD spectra suggested the
formation of 1 : 1 complexes, an observation that was further confirmed by electrospray
mass spectrometry. 1 H-NMR analysis in the absence or presence of ZnCl 2 indicates that
the b-peptide, which is present as a 14 -helix in methanol, is forced into a hairpin-turn
structure by Zn binding in water. In addition, the b-peptide with cystein and histidine resi-
dues positioned far apart from each other adopts a distorted turn structure in the presence
of Zn .
An alternative approach for mimicking natural metal-binding motifs is the use of
“peptoids” - N-substituted glycine oligomers. Peptoids have emerged as intriguing mim-
ics of polypeptides [47], particularly with respect to their ability to form well defined
folded architectures [41b]. Moreover, many peptoid sequences exhibit a remarkable pro-
pensity for folding even at small oligomer chain lengths [48]. Peptoid oligomers can be
synthesized efficiently by solid-phase methods, allowing the introduction of a variety of
side chains (Figure 11.19) [42], therefore enabling the coordinated display of multiple
chemical functionalities which can potentially emulate the active sites of proteins (e.g.,
metal-binding sites).
The group of Zuckermann described the introduction of a high-affinity zinc-binding
function into a peptoid, which consists of two helices bound together by a short peptide
coil, and demonstrated its folding into a two-helix bundle upon binding with a zinc ion
(Figure 11.20) [49]. Each helix was designed to contain a bulky chiral side chain in two-
thirds of the monomer positions, since these side chains are known to enforce helicity
[48a]. The side chains that were used - ( S )-N-(1-phenylethyl)glycine (Nspe), and ( S )-N-
7(p K a of histidine
¼
>
Figure 11.19 Two-step solid-phase synthesis of peptoids.
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