Noncovalent chirality sensing ensembles for the detection and reaction monitoring of amino acids, peptides, proteins, and aromatic drugs

Article abstract of DOI:10.1002/anie.201400718

Ternary complexes between the macrocyclic host cucurbit[8]uril, dicationic dyes, and chiral aromatic analytes afford strong induced circular dichroism (ICD) signals in the near-UV and visible regions. This allows for chirality sensing and peptide-sequence recognition in water at low micromolar analyte concentrations. The reversible and noncovalent mode of binding ensures an immediate response to concentration changes, which allows the real-time monitoring of chemical reactions. The introduced supramolecular method is likely to find applications in bioanalytical chemistry, especially enzyme assays, for drug-related analytical applications, and for continuous monitoring of enantioselective reactions, particularly asymmetric catalysis. Strong and diagnostic induced circular dichroism signals in the near-UV or visible region are obtained when chiral, optically transparent analytes bind to an achiral chemosensing ensemble composed of a macrocyclic host and dye. This affords a novel, supramolecular detection method for chiral aromatic analytes in water.

Full text of DOI:10.1002/anie.201400718

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Angewandte
Communications
DOI: 10.1002/anie.201400718
Host–Guest Chemistry
Noncovalent Chirality Sensing Ensembles for the Detection and
Reaction Monitoring of Amino Acids, Peptides, Proteins, and
Aromatic Drugs**
Frank Biedermann* and Werner M. Nau*
Abstract: Ternary complexes between the macrocyclic host
cucurbit[8]uril, dicationic dyes, and chiral aromatic analytes
afford strong induced circular dichroism (ICD) signals in the
near-UV and visible regions. This allows for chirality sensing
and peptide-sequence recognition in water at low micromolar
analyte concentrations. The reversible and noncovalent mode
of binding ensures an immediate response to concentration
changes, which allows the real-time monitoring of chemical
reactions. The introduced supramolecular method is likely to
find applications in bioanalytical chemistry, especially enzyme
assays, for drug-related analytical applications, and for con-
tinuous monitoring of enantioselective reactions, particularly
asymmetric catalysis.
signals fell in the far-UV region and/or required high
millimolar concentrations, both of which prevent practical
application. The supramolecular chirality sensing ensem-
bles which we introduce herein are assembled from an achiral
host and achiral dyes as auxiliary chromophores (Figure 1).
[
2a]
M
ost biological analytes are chiral, but transparent in the
visible spectrum. The combination of a chiral receptor with
a chromogenic signaling unit has, therefore, been the focus in
[
1]
the design of supramolecular chemosensing ensembles. The
addition of a chiral analyte leads either to a direct binding to
a chiral chromophoric receptor or to the displacement of an
Figure 1. The complexation of chiral analytes by a self-assembled,
achiral host·dye receptor converts a weak intrinsic CD signal in the far-
UV region into a strong ICD effect in the near-UV and visible regions.
[
1]
indicator dye from a chiral synthetic host. Regardless which
route is taken, it is the design of the stereodiscriminating
receptor which presents the main challenge, especially as
analyte detection in water is required. An alternative
approach to chirality sensing which has recently been receiv-
ing considerable attention exploits sensing by circular dichro-
The intrinsic CD signals of many chiral analytes, partic-
ularly amino acids, peptides, proteins, and carbohydrates as
well as synthetic drugs, are weak and lie in the far-UV region
(Figure 1, left). The addition of the achiral host·dye receptor
results in strong ICD signals emerging as a consequence of the
formation of a chiral host·dye·analyte complex (right). Our
supramolecular approach to chirality sensing has the follow-
ing advantages:
[
2]
ism (CD) probes, which undergo stoichiometric chemical
reactions, typically metal ligation, with the analyte. This
requires not only reactive functional groups (hydroxy or
amino) to be present but also sufficiently long reaction times.
The induction of CD through noncovalent interactions of
chiral analytes with achiral receptors could bypass both the
design of chiral hosts and the formation of covalent adducts.
Such noncovalent ICD probes have the potential to detect
a broad spectrum of analytes, including nonreative ones, and
to allow the monitoring of reactions, even of fast ones. Proof
of principle for detectable ICD effects through noncovalent
1) A large range of chiral aromatic compounds can be
detected and their chirality differentiated through oppo-
site ICD signals.
[4]
2) The ICD spectra, while challenging to predict, are
sufficiently diagnostic to distinguish different analytes,
for example, peptide sequences.
[
2b,3]
interactions with aromatic hosts exists,
but the Cotton
3) The magnitude of the optical response allows the highly
sensitive and selective (mm) detection of chiral analytes.
[
5]
4
) The ICD effects arise instantaneously, thus allowing
a real-time monitoring of (catalytic) reactions of chiral
analytes.
[*] Dr. F. Biedermann, Prof. Dr. W. M. Nau
School of Engineering and Science
Jacobs University Bremen, Campus Ring 1
5
) The signals of the ternary complex are shifted to the near-
UV or visible regions, which greatly improves compati-
bility with biological matrices and disposable (plastic)
microtiter plates required for screening.
28759 Bremen (Germany)
E-mail: frankbiedermann@daad-alumni.de
w.nau@jacobs-university.de
[**] We thank Suhang He for experimental help. This work was
supported by the DAAD and the DFG.
These assets, along with the operation in water, are essential
for analytical applications.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400718.
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Host–guest complexes of the barrel-shaped cucurbit-
[
6]
[
n]uril macrocycles (CBn, n = 5–14) have found widespread
interest for analytical applications in water, because the high
[
7]
affinity constants allow sensitive detection. The simulta-
neous inclusion of a dye and an analyte in the large cavity of
CB8 has been utilized for the optical detection of aromatic
[
8]
[9]
hydrocarbons, neurotransmitters, and Trp/Phe-containing
peptides.
[
10]
However, none of the existing methods are
capable of differentiating two enantiomers, because they
have identical affinities and, therefore, afford exactly the
same signals in the fluorescence, UV/Vis, ITC, and Raman
spectra. Our idea was that chiral analytes should afford
a strong and characteristic ICD signal with achiral CB8·dye
Figure 2. Chemical structures and schematic representations of the
macrocyclic host CB8 and the dyes.
[
11]
complexes.
The CB8-dye-chemosensing ensemble offers
a sufficiently large binding site to dock, with
the desirable broad selectivity, a diversity of
chiral analytes containing aromatic rings as
a common recognition motif.
The screening of a small library of
strongly absorbing dyes (see the Supporting
Information) afforded the dicationic dyes
MDAP, MDPP, and MVE as prime candi-
dates (Figure 2), because of their high bind-
ing affinity to CB8, compatibility with
a large range of analytes, and, most impor-
tantly, ICD responses as strong as in pre-
vious studies (see Tables S1–S3 in the Sup-
[3]
porting Information). Although a particu-
lar dye may be best suited for a specific
purpose, for example, to afford a strong ICD
band at a desired wavelength, the dyes could
be used interchangeably for many of the
following application examples.
Figure 3 shows all the analytes studied.
The amino acid derivative NAcTrpNH , for
2
example, shows a barely detectable intrinsic
CD signal near 280 nm at 40 mm (Figure 4a).
When the same analyte is added to the
preformed CB8·MDPP reporter pair (20 mm
each) a strong ICD signal appears, which
ranges up to 550 nm—the region in which
the dye absorbs. In general, ICD effects are
greatly enhanced by a constructive orbital
overlap, which ensures exciton coupling and
a
conformationally confined interaction
[
2a,12]
geometry.
Evidently, both conditions
are nicely fulfilled for the constrained face-
to-face arrangement of analyte and reporter
dye in the rigid CB8 cavity (Figure 1).
[
6c,13]
Figure 3. Chemical structures of the investigated chiral analytes.
The affinities of the structurally diverse,
3
more than 30 analytes ranged from 10 to
6
À1
11 À1 [14]
1
0 m (see Tables S1 and S2 in the Supporting Information),
ꢀ 10 m )
and, thereby, eliminates the ICD effect (Fig-
which generally allowed a highly sensitive detection. Binding
constants determined by ICD titrations corroborated those
obtained by UV/Vis titrations. In all cases, CB8 acts as an
indispensable template to assure the ICD effects; the
conclusive control experiment is the destruction of the
ure 4a). As expected, the use of an alternative reporter dye,
MDAP or MVE, led to a different ICD spectrum, but at
similarly low analyte concentrations (40–100 mm; see Fig-
ure S2 and Table S2 in the Supporting Information), as is
desirable for sensing in water.
CB8·MDPP·NAcTrpNH receptor–analyte complex through
the addition of memantine, which sequesters CB8 (Ka
Most optical sensing approaches based on a single recep-
tor afford a qualitatively similar response for structurally
2
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investigated. Again, clearly distinguishable ICD spectra
resulted (Figure 4b; see also Figures S3 and S4, and
Table S1 in the Supporting Information) at micromolar
concentrations. Internal Trp residues also produce character-
istic ICD signatures (see Figure S3 and Table S1 in the
Supporting Information). Indeed, a single Trp residue is
sufficient for peptide sensing, as demonstrated for the cyclic
peptidic hormone somatostatin (Figure 3). Strikingly, the ICD
pattern is sufficiently characteristic, in comparison to the
effects for smaller model peptides (see Figure S3 and Table S1
in the Supporting Information), to pinpoint the Trp rather
than the two Phe residues as the preferred binding site in
somatostatin. This is, indeed, an important piece of solution-
phase structural information, which is otherwise only acces-
sible by NMR spectroscopy at much higher concentrations.
We are unaware of any other receptor that gives rise to such
distinctive optical responses when binding analogous pep-
tides. Proteomics ideas for sequence recognition and peptide
fingerprinting using principle component and discriminant
[
15]
analysis come to mind. Even without this, one can readily
differentiate N-terminal Trp-functionalized heptapeptides
(
Figure 3) from each other at ꢁ 50 mm (Figure 4b). Peptides
starting with TrpGly, TrpVal, TrpAsp, and TrpPro show
characteristic Cotton bands; only the starting sequences
TrpAla, TrpGlu, and TrpLeu resulted in very similar ICD
[
16]
spectra.
Carbohydrates also resist direct detection or discrimina-
tion by optical spectroscopy. Unfortunately, they do not bind
to the CB8·dye complexes in their unmodified form either.
Nevertheless, phenyl-b-d-galactose and phenyl-b-d-glucose
are complexed tightly (see Tables S1 and S2 in the Supporting
Information). These two epimers display identical spectra in
the far-UV region in water; even their intrinsic CD spectra
are virtually the same. However, in the presence of the
CB8·MDAP receptor, their strong ICD spectra, with well-
defined isodichroic points (see Figure S7 in the Supporting
Information), can be readily discriminated. Interestingly, the
effects for the biomolecular analytes are large, even though
the stereogenic centers themselves are not immersed in the
host cavity.
Figure 4. Examples of chirality sensing. a) CD spectra of NAcTrpNH2
40 mm, black line), after addition of CB8·MDPP (20 mm in H O, red
(
2
The vast majority (ca 80%) of oral drugs contain at least
line), and subsequent CB8 sequestering by memantine as a competitive
binder (60 mm, green line). b) CD spectra of CB8·MDPP (20 mm in
H O) in the presence of different Trp(Xaa) NH heptapeptides
[17]
one aromatic residue, which similarly serves as an anchor
for our receptors. For example, the chiral naphthol-type drug
propranolol (Figure 3) displays an absorption in the near-UV
region, but its intrinsic CD signals are very weak, because of
2
6
2
(
ꢂ3 equiv). c) CD spectra of insulin (50 mm, pH 2.7) in the presence
of CB8·MDPP (20 mm) and subsequent CB8 sequestering by meman-
tine (60 mm).
[
4,12a]
its conformational flexibility, which scrambles CD effects.
Clear Cotton bands emerged in the presence of the CB8·dye
reporter pair (see Tables S1 and S2 in the Supporting
Information), as was the case for penicillin G and ampicillin
(see Figure S4 in the Supporting Information). The method
can logically be expanded to determine the enantiomeric
excess of drugs because 1) racemic mixtures do not produce
any ICD response (Figure 5a) and 2) because two enantio-
mers must display identical binding to the achiral receptor but
opposite ICD effects (see Figure S3 in the Supporting
related analytes, for example, a net fluorescence quenching,
which prevents their differentiation. This is invariably the
case for the popular indicator displacement assays, for which
the spectral response of the liberated dye does not report on
the structure of the analyte. In contrast, different derivatives
of the amino acids Trp and Phe gave distinct ICD spectra with
our chemosensing ensemble (see Figures S3 and S4 as well as
Tables S1 and S2 in the Supporting Information). Encouraged
by these results, a small library of dipeptides, tripeptides, and
heptapeptides with N- or C-terminal Trp/Phe residues was
[
2a,18]
Information). This offers a very important application.
We also tested the compatibility of the ICD sensing
platform with insulin. This protein target possesses a sterically
[
7c]
accessible N-terminal Phe residue in its B chain; its six
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because the aromatic amino acids of these (and most other)
proteins are shielded in their hydrophobic core.
The enhanced ICD effects observed for the various
analytes establish a new method for the sensitive, label-free
monitoring of chemical reactions in real time, such as
enzymatic conversions involving chiral metabolites. This is
made possible by the fact that the noncovalent binding to the
supramolecular receptor is reversible and shows fast
[
5]
exchange kinetics, which differentiates our approach from
complementary chiroptical methods involving covalent
[
2]
adducts. The dynamic response (which probes the reaction
progress through a complexation equilibrium between ana-
lyte and reporter pair) also allows nonstoichiometric amounts
of the host (and even excess dye) to be used. We now provide
compelling proof of this novel concept.
1
) We have followed in situ the b-galactosidase-mediated
enzymatic hydrolysis of phenyl-b-d-galactose. As
expected, its cleavage into phenol and galactose was
accompanied by a decrease in the ICD signal, as the
emerging receptor·phenol complex is achiral (see Fig-
ure S7 in the Supporting Information).
2
) Although BSA gives no ICD effect (see above), the
addition of the protease pepsin destroys its compact
tertiary structure such that the aromatic residues become
accessible to the receptor. This structural and chemical
change can be continuously monitored through emerging
ICD effects with the reporter pair (see Figure S8 in the
Supporting Information).
3
) Since the ICD patterns of peptides are sequence-selective,
a new line of label-free enzyme assays can be set up, which
remain in high demand, for example, for exopeptidases
[
19]
such as carboxypeptidase A.
This enzyme cleaves C-
terminal Phe residues preferentially, as could be directly
monitored when the digestion of the model substrate
hippuryl-Phe was monitored by the ICD assay (Fig-
ure 5b).
4
5
) Likewise, leucine aminopeptidase (LAP) was successfully
employed for peptide digestion, for example, of AlaPhe
into Ala and Phe (see Figure S9 in the Supporting
Information) or of GlyTrpGly, which was followed
through both near-UV and visible ICD bands (see Fig-
ure S10 in the Supporting Information).
) Chirogenesis can also be readily followed. When starting
with a racemic mixture of a substrate in the presence of the
achiral chromophoric receptor, ICD effects should arise
upon any enantiospecific conversion. Indeed, enzymatic
digestion of racemic Gly-d /l -Phe with LAP led to the
appearance of the characteristic dichroic fingerprint of l-
Phe, because only the Gly-l-Phe dipeptide was hydrolyzed
Figure 5. Examples of reaction monitoring. a) CD spectra of
CB8·MDPP (20 mm) in the presence of racemic Gly-d/l-Phe, before
and after its enzymatic hydrolysis by leucine aminopeptidase (LAP) at
pH 7.8. b) Kinetic trace for the hydrolysis of Hippuryl-Phe (160 mm) by
carboxypeptidase A at pH 7.8. The reaction progress was monitored by
CD (329 nm) in the presence of CB8·MDPP (20 mm, red line) and, as
a control, directly by UV/Vis spectroscopy (254 nm, black line).
c) Racemization of (S)-1-phenylethanol (0.08m in H O) with amberlyst-
2
H at 658C, monitored by the addition of reaction mixture aliquots
(
10 mL, 400 mm final concentration) to CB8·MVE (40 mm).
(Figure 5a, and see Figure S11 in the Supporting Infor-
internal Phe or Tyr residues are buried inside. Addition of the
CB8·MDPP receptor to insulin (50 mm) indeed led to a very
distinctive ICD band at 335 nm (Figure 4c, and see Table S1
in the Supporting Information). Disassembly of the receptor–
insulin complex by memantine diminished the ICD bands,
and thus nonspecific competitive binding of the dye to the
protein does not apply (Figure 4c). Bovine serum albumin
mation).
Of major practical interest is the fact that the ICD method
allowed us to monitor each of these enzymatic reactions in the
near-UV region (> 310 nm), thereby bypassing biological
matrix effects as a result of absorbing and/or CD-active
impurities or additives. The latter cannot be avoided when
applying alternative far-UV assays—some of which were also
performed as controls to double-check the absolute kinetics
(
BSA) and lysozyme were studied as negative controls; here,
no ICD effects were observed in the presence of the receptor
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obtained by the ICD assays (Figure 5b, and see Figure S8 in
the Supporting Information). The agreement between both
types of assays confirmed that the two additives (host and
dye) did not strongly influence the enzymatic activity.
We previously introduced supramolecular tandem assays
as time-resolved variants of fluorescent indicator-displace-
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racemization with ease (Figure 5c), in fact for a heteroge-
neous catalysis. An amberlyst-catalyzed racemization was
selected as a prototype reaction because of its industrial
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blocks. As an additional difference, instead of measuring
the racemization of (S)-1-phenylethanol directly in the
reaction mixture, we preferred to draw aliquots and add
them to a cuvette containing the sensing ensemble, the
CB8·MVE pair in this case. The resulting decrease in the ICD
signal at 348 nm can be directly correlated to the kinetics of
the racemization reaction, thus providing a more sensitive
detection tool than direct measurement of chiroptical sub-
strate properties. This final application example illustrates
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In conclusion, we have developed a versatile method
based on self-assembled, achiral host–dye pairs that report
micromolar concentrations of water-soluble chiral analytes
through ICD effects in the preferred near-UVor visible range.
The method can be adapted to many structurally related
analytes, in our case analytes with sterically accessible
aromatic recognition motifs. It is applicable to many biomol-
ecules as well as synthetic drugs and can be transfered from
simple analyte detection to the sequence recognition of
peptides. Most importantly, we introduce the use of supra-
molecular chirality sensing ensembles for monitoring enzy-
matic as well as other catalytic reactions. This has broad
application potential, including analyte detection in flow
systems, because the chirality and affinity of the reactant or
product are the only prerequisites for utilizing the method.
Several achiral water-soluble hosts, including macrocycles
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[
[
[
[
[
3b,7d,22]
with covalently linked chromophores,
are known, and
these have a similar potential for chirality sensing.
Received: January 22, 2014
Published online: April 9, 2014
Keywords: circular dichroism · cucurbiturils · dyes ·
.
macrocycles · sequence recognition · supramolecular chemistry
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[
[
16] It must be noted that none of the peptides or their complexes
could be distinguished by UV/Vis spectroscopy (see Figure S6 in
the Supporting Information). In addition, the CD bands of the
peptides—without receptor—were very weak, noncharacteristic,
and, more adversely, occurred at an unattractive wavelength for
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