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Switch Peptides In Statu Nascendi Induction of Conformational Transitions Relevant to Degenerative Diseases.

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Protein Folding
Switch Peptides In Statu Nascendi: Induction of
Conformational Transitions Relevant to
Degenerative Diseases**
Manfred Mutter,* Arunan Chandravarkar,
Christine Boyat, John Lopez, Sonia Dos Santos,
Bhubaneswar Mandal, Richard Mimna, Karine Murat,
Luc Patiny, Lydiane Sauc$de, and Gabriele Tuchscherer
Aspects of conformational transitions, folding, and misfolding
of peptides and proteins have moved into the center of
interest in various domains of research at the interface of
chemistry, biology, and medicine because of their impact on
neurodegenerative diseases.[1] For example, recent research
suggests that conformational transitions of soluble amyloid b
precursor molecules into aggregated, b-sheet-type forms play
a key role in the deposition of cerebral amyloid plaques
[*] Prof. M. Mutter, Dr. A. Chandravarkar, Dr. C. Boyat, Dr. J. Lopez,
Dipl.-Chem. S. Dos Santos, Dipl.-Chem. B. Mandal,
Dipl.-Chem. R. Mimna, Dipl.-Chem. K. Murat, Dr. L. Patiny,
Dipl.-Chem. L. Sauc&de, Dr. G. Tuchscherer
Institute of Chemical Sciences and Engineering (ISIC)
Swiss Federal Institute of Technology, EPFL-BCH
1015 Lausanne (Switzerland)
Fax: (+ 41) 21-693-9415
[**] This work was supported by the Swiss National Science Foundation.
The Ncap peptidomimetic was a generous gift from Prof. Klaus
M>ller, Hoffman-La Roche, Basel, Switzerland.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200454045
Angew. Chem. Int. Ed. 2004, 43, 4172 –4178
characteristic of Alzheimer!s disease.[2] Similarly, a-helix-tob-sheet transitions are thought to be at the molecular origin of
the transformation of the physiological PrPc form of the prion
protein into pathological PrPsc.[3] Due to the intimate relationship between sequence, secondary structure, and physicochemical properties, studies on oligo- and polypeptides[4]
exhibiting high propensity for b-sheet formation are severely
limited by the intrinsic tendency of peptides for self-association and irreversible aggregation.[1] Consequently, b-sheetand fibril-forming processes related to degenerative diseases
remain elusive, as delineation of structure nucleation or
inhibition is a formidable task, often yielding contradictory
Based on concepts for inducing and disrupting peptide
structure and function,[5–7] we describe here a novel class of
switch peptides.[8] With these compounds we can study folding
events in the dynamic process of structure onset and
evolution, that is, “in statu nascendi” (ISN) of the molecule.
We used chemical synthesis to construct modular switch
peptides (Figure 1) consisting of three segments: a conforma-
in statu nascendi
pH 7
chemical synthesis
off O
Figure 1. ISN-induced conformational transitions. By removal of Y
(enzymatic or by change of pH), X!N acyl migration is triggered.
This leads to the formation of a regular peptide bond between s and P
and results in a change in conformation, typically from a flexible
random-coil (Soff ) to a folded (Son) state. By application of peptidomimetics and templating effects, these conformation changes can be
used to study the s-induced nucleation (A), onset (B), and disruption
(C) of secondary and tertiary structures.
tion induction unit (s), a switch element (S) and a target
peptide (P, depending on its function also termed as host,
ligand, or native peptide). A major conceptual feature here is
that the conformational impact of s on the target peptide P is
switched on by the intramolecular X!N migration (X = O, S)
of an acyl residue.
Acyl-transfer reactions have been the subject of extensive
mechanistic studies,[9, 10] and their role in protein biosynthesis
and splicing,[9, 11] peptide synthesis and solubilization,[12]
Angew. Chem. Int. Ed. 2004, 43, 4172 –4178
prodrug design,[13] and native chemoselective ligation strategies[9, 14] has attracted considerable attention recently. For the
purpose at hand, induced intramolecular X!N acyl-transfer
reactions as the key step for the onset of structure and
function offer several appealing features:
a) The precursor molecules (“switch peptides”), structurally
corresponding to N(Y)-protected O/S-acyl isopeptides
(also termed O/S-peptides[15]) are readily accessible by
chemical synthesis[16] and show appropriate stability and
solubility in aqueous buffers (presence of a polar or
charged group in element S), facilitating purification steps
prior to acyl migration.
b) The insertion of an S element exhibiting a flexible
nonpeptidic linkage interrupts the hydrogen-bonding
pattern of the regular amide backbone and deactivates
the conformational effects of the inducer s upon peptide
P.[17] Depending on the state of S (“on” or “off”) the
peptide assumes one of two distinct conformational states
(Son and Soff) which have different properties.
c) For triggering the X!N acyl migration reaction in situ, a
broad palette of methodologies can be envisioned.[18] We
developed enzymatically cleavable N-protecting groups
(Y) as prototypes for in vitro and in vivo applications.
Alternatively, we also apply pH-induced acyl-transfer
reactions as a well-established procedure.[11a, 13]
d) The native peptide bond is formed very fast by acyl
migration following first-order kinetics,[9] setting off
structure and function.
We demonstrate the concept outlined in Figure 1 for the
nucleation, disruption, and onset of secondary and tertiary
structures of designed and native peptides of therapeutic
In strategy A, synthetic building blocks[5, 19] and peptidomimetics designed to overcome the entropically unfavorable
nucleation energy for polypeptide folding[4a] may serve as the
induction unit s for the ISN nucleation of secondary
In our first studies we assembled a highly constrained
peptidomimetic (Ncap[19e]) as the induction unit s on a parent
peptide P (Ia, Table 1). In the absence of the nucleation effect
(Soff), Ia adopts predominantly a random-coil conformation
(CD spectrum, Figure 2 a). When the pH is adjusted to 7, the
O!N acyl migration is triggered (migration half-life t1/2 ~
25 min, inset Figure 2 a), and the helix nucleating property
of the Ncap unit is set off (ISN, Son). This results in a
spontaneous conformational transition to an a-helical structure (percentage of the helix content corresponding to degree
of migration), which is evident from characteristic Cotton
effects in the CD spectra. For comparison we assembled Ib
which features an acetyl group as the induction unit s in an
otherwise identical peptide sequence. In contrast to Ia, switch
peptide Ib shows upon acyl migration (t1/2 < 5 min) a conformational transition from a random-coil (Soff) to a b-sheet
structure (Son) (Figure 2 b). This points out the intrinsic
conformational preference of the amphiphilic oligopeptide
(Ser-Leu)n[20] and the pronounced helix-nucleation power of
the Ncap in Ia. In view of the large pool of synthetic units such
as topological templates, scaffolds, and peptidomimetics at
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Table 1: Switch peptides prepared by the assembly of modules P and s
by switch element S (Scheme 1) according to Figure 1.
Switch peptide Y
[a] Cys (IVc), Thr (V). [b]
Y–Ser[a] (s)–P
Ac-(SL)2-Ab (14–20)
Ac-NPY (21–31)[f ]
Ab (21–24)-SLG-NH2[d]
NPY (33–36)[g]
. [c]
hand today,[5, 19] their use as induction units for the in situ
transformation of conformational states, for example, potentially b-sheet-forming oligopeptides to helical structures as
shown above may offer a powerful tool for reversing
processes relevant in degenerative diseases.
When individual peptide blocks s and P are used having a
chain length n below the critical value for the formation of
helix (nc, a) or b-sheet (nc, b) structures,[4, 20] the resulting
switch peptide inherently adopts a nonfolded flexible conformation (Soff). When a regular peptide bond is established
between s and P upon acyl migration (Son), the peptide attains
the critical chain length for secondary-structure formation,
thus initiating sequence-dependent conformational transitions.
To further test this concept, we assembled oligopeptides
(Leu-Ser)n (II in Table 1)[20a] and amyloid-derived sequences
(III),[2, 6] both exhibiting high potential for b-sheet and fibril
formation as switch peptides. As revealed by CD, IR, and EM
studies, the insertion of a switch element S results in the
disruption of ordered structures. When the pH is adjusted to
trigger the acyl-transfer reaction, ISN-induced conformational transitions from random-coil to b-sheet structures are
observed, which are accompanied by a significant decrease in
peptide solubility (Figure 3 a, Figure 4 a).[5, 19] A reference
peptide of IIa with irreversible N-protection (Y = Ac) shows
pH-independent random-coil conformations, confirming that
the observed transition originates exclusively from the s
induction by acyl migration.
Since acyl migration can be initiated in various ways, the
rate of structure transition can be modulated over a broad
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 2. ISN-induced conformational transitions monitored by CD
spectroscopy. a) Upon pH-induced acyl migration, switch peptide Ia
transforms (inset: time course of migration monitored by HPLC) from
a random-coil (Soff ) to an a-helical state (Son). b) In contrast, Ib shows
under identical experimental conditions the transition from a randomcoil (Soff ) to a b-sheet (Son) (inset: time course (best fit to experimental
data points) of conformational transition (CT) taking the normalized
VM values at l = 218 nm for Soff (0 %) and Son (100 %) as reference.
timescale (t1/2 < 1 min to several hours). Correlating t1/2 values
of migration (monitored by HPLC) and onset of secondary
structure (monitored by CD or other spectroscopic methods)
provides access to quantitative data on the kinetics and
experimental parameters of b-sheet formation.[27] For switch
peptide IIa formation of the b-sheet structure has a t1/2 value
of 38 min at a given starting concentration (7.2 E 106 m) and
pH (6.6, curve 3 in Figure 3 b). In contrast, at physiological
pH, the corresponding t1/2 value shifts to 10 min (Figure 3 c). For tailoring the onset of conformational transitions
in vitro, the use of enzymatically cleavable N-protecting
groups (Y) is a versatile alternative as exemplified for trypsin-,
esterase-, and pyroglutamate aminopeptidase-induced acyl
migrations (E1–E3, Figure 3 d). Most notably, all enzymes
used here showed high specificity for the cleavage site at the
N-terminus of parent peptide P (Arg-Ser, E1; acetyl ester
bond in Acoeoc, E2; pGlu-Ser, E3).[21]
We applied host–guest techniques[4e] for mimicking the
structural environment of peptides “excised” from their
native polypeptide. For example, after incorporation into a
Angew. Chem. Int. Ed. 2004, 43, 4172 –4178
Figure 3. The onset of b-sheet structure in statu nascendi of IIa. a) CD monitoring
of the conformational transition upon acyl migration (inset: HPLC) from a
random-coil (Soff ) to a b-sheet (Son) conformation at pH 6.6 (c = 7.2 H 106 m).
Dependence of CT (see legend to Figure 2) on b) concentration at pH 6.6 (1:
c = 2.9 H 105 m; 2: c = 1.45 H 105 m; 3: c = 7.2 H 106 m; 4: = 3.6 H 106 m); c) pH
(concentration of IIa in Soff state: c = 8 H 106 m); d) type of enzymatic cleavage site
(IId (trypsin, E1), IIb (esterase, E2), IIc (pyroglutamate aminopeptidase, E3)).
b-sheet-promoting host peptide (switch peptides IIIa, b), the
amyloid b (14–24) peptide and islet-protein-derived sequence
NFGAIL,[1, 6] undergo upon acyl migration a conformational
transition from random-coil to b-sheet structure, paralleled by
the onset of fibril formation (Figure 4 a). In the evaluation of
the impact of external factors (e.g. inhibitors, b-sheet breakers) upon the critical concentration for the evolution of bsheet structures (Figure 3 b–d) as nuclei for fibril formation,[2, 6, 22] host–guest switch peptides may serve as a diagnostic kit system of considerable therapeutic potential.
For the design of potentially amyloid-fibril-inhibiting or
-disrupting compounds, the concept of “separating” recognition (s inactivated) and functional (s activated) states
appears of particular relevance. With this objective in mind,
Angew. Chem. Int. Ed. 2004, 43, 4172 –4178
Figure 4. Host–guest techniques for studying conformational transitions. a) CD of the ISN-induced conformational transition from
random-coil (Soff, pH 4.4) to b-sheet (Son, pH 7) for IIIa (1’, 1) and IIIb
(2’, 2). b) CD spectrum of IVa in the absence (1) and presence (2) of a
template b-sheet (1:1 mixture of IVa (Soff ) and IIa (Son)) and (3) of IIa
(Son) in the presence of IVa (Son). c) Electron microscopic images of
peptide IIa in the Soff (top) and Son state after 2 d. d) Kinetics of the
acyl migration of IVa (1), IVc (2), IVb (3).
we assembled pseudoproline (YPro)-containing building
blocks as induction units s for b-sheet breaking and ligands
P (strategy C, Figure 1, switch peptides IVa–c). Due to the
conformational decoupling (Soff) of s and P, the intrinsic bsheet potential of peptides P should promote their association
to host b-sheets or fibrils in a first step. For example, the
amphiphilic oligopeptide P in IVa with n < nc, b adopts a
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
random-coil conformation at pH 7 but is transformed into a bsheet in the presence of a host oligopeptide (n > nc, b) serving
as template (Figure 4 b). Similarly, the amyloid-derived
peptides P (IVb, c) may serve as ligands for amyloid-template
recognition. In triggering the acyl migration, that is, in
establishing the regular peptide backbone, the well-known
structure disrupting (“b-breaking”) effect of the YPro system
(featuring a cis-amide bond)[6a, 7b, 23] is set off, as revealed by
the presence of random-coil conformations in peptides IVa–c
(Son, Figure 4 b).
Interestingly, the YPro-containing switch peptides
undergo migration at significantly different rates (Figure 4 d).
The cysteine-containing peptide IVc has a stronger tendency
for intramolecular acyl migration than the serine-containing
IVb. Preliminary in vitro studies on the amyloid-fibrildisrupting potential[6a, 24] of these peptides point to some
interesting therapeutic applications.[25]
Finally, we apply the ISN induction of conformational
transitions for the onset of biological function, making use of
structure–activity relationship studies on neuropeptide Y
(NPY) and its shorter analogues.[26] As shown previously,
the C-terminal peptide NPY (21–36) has the minimum chain
length for retaining significant binding capacity to NPY
receptor Y2, notably in a helical state as the bioactive
conformation. When the two peptide blocks NPY (21–31) and
NPY (33–36), both with n < nc,a, are conformationally
decoupled by insertion of switch element S (derived from
Thr32), the resulting switch peptide V adopts a random-coil
conformation and shows no binding to Y2 (IC50 @ 10 mm [21]).
When native NPY (21–36) is triggered by O!N acyl
migration (t1/2 = 20 min at pH 5.8, t1/2 < 2 min at physiological
pH), a random-coil-to-helix transition is observed (typical CD
curves, Figure 5), paralleled by the onset of biological
function (IC50 = 0.8 nm).
We expanded this strategy to polypeptides of higher
complexity. Native amyloid b (1–42),[22a] assembled as switch
peptide (featuring multiple S elements), exhibits a randomcoil structure and excellent solubility during peptide synthesis
and purification, in contrast to the native molecule.[27]
In conclusion, the in statu nascendi (ISN) induction of
structure and function provides a novel tool for the study of
Figure 5. ISN induction of structure and function. CD spectrum of the
course of a-helix formation of V. Inset: HPLC monitoring of the acyl
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
major conformational transitions observed in native peptides
and proteins. Through application of alternative methodologies for monitoring conformational transitions on variable
timescales, the molecular origin of dynamic conformational
processes leading to self-association, polymerization, and
irreversible aggregation as early events in degenerative
diseases becomes accessible. This opens challenging perspectives in molecular recognition, biosensor technology, and drug
Experimental Section
Peptide synthesis: Switch peptides I–V were synthesized according to
standard procedures of solid-phase peptide synthesis (SPPS)[28]
following the Fmoc/tBu strategy on Rink-4-methylbenzhydrylamine)
(MBHA) resin (step 1 in Scheme 1).[28c] After removal of the N-
Scheme 1. Strategy for the chemical synthesis of switch peptides (see
Figure 1 and Table 1).
terminal Fmoc protection with 20 % piperidine in DMF, amino acid
coupling (2 equiv) was mediated by PyBOP or DIC/HOBT activation
in the presence of DIPEA and repeated if necessary. After cleavage
of the peptides from the resin with TFA/TIS/H2O (95/2.5/2.5), all
peptides were subjected to RP-HPLC purification and characterized
by amino acid analysis and ESI-MS. DIC = diisopropylcarbodiimide,
DMF = dimethylformamide,
HOBt = 1-hydroxybenzotriazole,
PyBOP = 1-benzotriazolyloxytris(pyrrolidino)phosphonium hexafluorophosphate,
TFA = trifluoroacetic acid, TIS = triisopropylsilane.
The N-terminal Ser residue of target peptide P (switch element S,
steps 2–4 in Scheme 1, variant A) was coupled as an a-Boc-protected
residue (2 equiv Boc-Ser-OH, PyBOP, DIPEA in DMF). For sidechain esterification of Ser, a Na-Fmoc-protected amino acid (3 equiv)
was coupled with DIC (3 equiv) and DMAP (0.1 equiv) in anhydrous
dichloromethane. Alternatively, the switch element S was introduced
as an N(Y’)-protected O-acyl isodipeptide[16a, 21] and incorporated as a
building block in SPPS according to Scheme 1 (variant B). DMAP =
Angew. Chem. Int. Ed. 2004, 43, 4172 –4178
Triggering O!N acyl migrations (step 5 in Scheme 1): pH
Induction (Y1): Stock solutions of switch peptides were prepared
(103 m in doubly distilled water, pH < 5). An aliquot was removed
and the pH adjusted by addition of sodium phosphate buffer
(100 mmol). To monitor O!N acyl migration by HPLC, 20-mL
aliquots were removed at regular time intervals, quenched by adding
0.2 n HCl, and injected.
Enzymatic triggering (Y2–4): The corresponding peptide (1 mg)
was dissolved in 500 mL sodium phosphate buffer (pH 7.4) at 37 8C
and the appropriate enzyme added (0.1 mg trypsin (Y3); 50 mL
pyroglutamate aminopeptidase (Y4); few beads of immobilized
esterase (Y2)). The reaction was monitored by HPLC as described
CD spectra were recorded on a Jasco J-810 spectropolarimeter
with a Jasco–Peltier-type temperature controller (model PFD-425S)
at a concentration of 105 m in quartz cells (Hellma, QS, strain-free
suprasil; path length 0.1 cm). Data were collected as an average of
three scans of 2.0-nm bandwidth.
ESI-mass analysis was carried out on a Finnigan MAT SSQ 710C
spectrometer equipped with an IBM PS/2 95 XP 86 (software
Technivent Vector II) in positive ionization mode.
Received: February 17, 2004 [Z54045]
Keywords: Alzheimer’s disease · circular dichroism ·
protein folding · protein structures · switch peptides
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