Switchable catalytic activity: Selenium-containing peptides with redox-controllable self-assembly properties

Article abstract of DOI:10.1002/anie.201303199

Mimicking nature: The reversible formation of self-assembled nanostructures of selenium-containing peptides can be controlled by redox triggers (see scheme, VC=vitamin C). As a consequence, the catalytic activity of these peptides is switchable. These res

Full text of DOI:10.1002/anie.201303199

Angewandte
Chemie
Communications
Self-Assembly
X. Miao, W. Cao, W. Zheng, J. Wang,
X. Zhang, J. Gao, C. Yang, D. Kong,*
H. Xu,* L. Wang,
Z. Yang*
&&&& — &&&&
Switchable Catalytic Activity: Selenium-
Containing Peptides with Redox-
Controllable Self-Assembly Properties
Mimicking nature: The reversible forma-
tion of self-assembled nanostructures of
selenium-containing peptides can be
controlled by redox triggers (see scheme,
VC=vitamin C). As a consequence, the
catalytic activity of these peptides is
switchable. These results should lead to
the development of nature-mimicking
smart materials with promising proper-
ties.
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DOI: 10.1002/anie.201303199
Self-Assembly
Switchable Catalytic Activity: Selenium-Containing Peptides with
Redox-Controllable Self-Assembly Properties**
Xiaoming Miao, Wei Cao, Wenting Zheng, Jingyu Wang, Xiaoli Zhang, Jie Gao,
Chengbiao Yang, Deling Kong,* Huaping Xu,* Ling Wang, and Zhimou Yang*
Self-assembly is abundant in nature, ranging from relatively
simple systems, such as lipid bilayers in cell membranes and
the double-helical DNA structure, to the complex structures
of organs. Many of these natural assemblies are dynamic and
their formation is reversible, and extensive research efforts
were recently made to develop smart materials by mimicking
these dynamic self-assembly systems and their reversible
formation.[1,2] For instance, Van Esch and co-workers devel-
oped a dissipative-gel system by using a chemical fuel.[3] The
phosphatase/kinase switch widely used in biological systems
to regulate protein activity and protein–protein interactions
has also been applied to control the self-assembly of block
polymers, polymer–polypeptide hybrids, and peptides.[4] In
order to form reversible-self-assembly systems, external
stimuli are needed, which are usually the pH value, temper-
ature, sonication, light irradiation, and additives.[5,6] Among
these stimuli, light irradiation is probably the most reliable
and biocompatible one. Reversible self-assembly systems
based on photoisomerizations have been widely studied and
reported, including those of low-molecular-weight molecules
and polymers.[7,8] However, most of these methods cannot be
applied in vivo, as our bodies have to maintain a relatively
steady physical environment to function. Developing alter-
native and complementary strategies that are capable of
reversibly switching bioactivity in vivo is in high demand.
Redox systems (e.g., NADH/NAD) have been widely
used to regulate various biological activities, the disassembly
of polymer micelles and nanogels, and the release of bioactive
molecules.[9] Inspired by these examples, we developed the
molecular-hydrogel system of selenium-containing peptides
with redox-controllable and reversible self-assembly and
catalytic activity. Recently, the groups of Xu and Zhang
developed a series of selenide- or diselenide-containing
polymers with redox-controllable self-assembly properties.[10]
The reversible transformation between selenide and selen-
oxide was triggered by the addition of vitamin C (VC) and
H2O2 (0.1 wt%). Vitamin C is biocompatible and the small
difference in the chemical structure of selenide and selen-
oxide leads to huge differences in solubility and self-assembly
properties of the polymers. Therefore, these systems have
shown promising potential for controlled drug delivery and
the generation of nature-mimicking systems. Stimulated by
the achievements in redox-controllable self-assembly sys-
tems[1,6,8] and self-assembly peptide systems,[11] we opted to
develop selenium-containing peptide systems with redox-
controllable self-assembly propensity. Specifically, we
intended to show that such redox control can regulate the
catalytic activity of histidine-containing peptides by grafting
the histidine to the selenium-containing peptides with differ-
ent self-assembled nanostructures. We also planned to
develop a biocompatible method for molecular hydrogelation
by using VC to convert peptides that contain selenoxide to
their reduced forms of selenide. In order to achieve these
goals, we first designed compound 1 (Figure 1) containing the
selenoxide group that could be reduced to selenide by VC,
leading to the formation of compound 2, which is less soluble
in aqueous solutions. With the assistance of Phe-Phe (FF),
compounds 1 and 2 might self-assemble into different kinds of
nanostructures.
The synthetic route for compounds 1 and 2 is shown in
Scheme S1 in the Supporting Information. First, 4-(phenyl-
selanyl)butanoic acid was synthesized in two steps in solution
with a total yield of 41%. It was then used in solid-phase
peptide synthesis (SPPS) to obtain compound 2. Pure
compound 2, which was obtained by high-performance
liquid chromatography (HPLC), was oxidized with H2O2
(30 wt%, 2 equiv with regard to compound 2) to produce
compound 1. This product could be solubilized in phosphate-
buffered saline (PBS, pH 6.0) at concentrations lower than
3.0 wt% (30 mgmLÀ1). A solution of compound 1 (1.0 wt%)
in PBS could be converted to a hydrogel upon the addition of
VC (1 equiv, final concentration of VC = 0.18 wt%; Figure 1).
The minimum concentration for gelation of compound 1 was
0.45 wt% when it was treated with 1 equivalent of VC.
[*] X. Miao, Dr. L. Wang, Prof. Z. Yang
State Key Laboratory of Medicinal Chemical Biology and
College of Pharmacy, Nankai University
Tianjin 300071 (P. R. China)
E-mail: yangzm@nankai.edu.cn
Homepage: http://yang-lab.org
W. Cao, Prof. H. Xu
Key Lab of Organic Optoelectronics and Molecular Engineering
Department of Chemistry, Tsinghua University
Beijing 100084 (P. R. China)
E-mail: xuhuaping@tsinghua.edu.cn
W. Zheng, J. Wang, X. Zhang, J. Gao, C. Yang, Prof. D. Kong,
Prof. Z. Yang
State Key Laboratory of Medicinal Chemical Biology and
College of Life Sciences, Nankai University
Tianjin 300071 (P. R. China)
E-mail: kongdeling@nankai.edu.cn
[**] The authors acknowledge Prof. Yang Liu (Tsinghua University) for
his kind discussion on electrochemistry measurements. This work
was supported by the NSFC (51222303, 21074066, and 51003049)
and the National Basic Research Program of China
(2013CB834502).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303199.
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Figure 1. Chemical structures of selenium-containing peptides and
optical images of a solution of 1 in PBS (1.0 wt%, pH 6.0) and a gel
formed by treating the solution of 1 with vitamin C (1 equiv; the
reversible transformation between 1 and 2 can be controlled by using
vitamin C and H2O2).
Figure 2. A) Illustration of the redox-triggered transformation between
micelles and nanofibers; and TEM images of B) the solution of 1 in
PBS (1.0 wt%) and C) the hydrogel resulting from the treatment of
this solution with of VC (1 equiv; image taken after 24 h treatment).
The conversion from compound 1 to compound 2 and the
mechanical properties of the hydrogel were analyzed by LC-
MS and rheology, respectively. The LC-MS results (Fig-
ure S14) indicated that 1 was gradually converted to 2 by
1 equivalent of VC in PBS at 378C. The conversion reached
an equilibrium after about 7 hours with a conversion of about
65%. For the solution containing 1.0 wt% of 1 and 1 equiv-
alent of VC, it took about 6 hours to forma a hydrogel, and
the conversion was about 59% at the gelling point. The
minimum VC concentration to trigger the formation of
a hydrogel from a solution containing 1.0 wt% of 1 was
about 0.05 wt% (0.28 equiv with regard to 1). An increase in
the concentrations of VC or 1 resulted in shorter gelation
times (Table S1). The resulting hydrogel could be converted
back to a solution by the addition of H2O2 (Figure 1, and
Figure S20 in the Supporting Information). This sol-gel-sol
cycle could be repeated for at least three times without
obvious decomposition of the compounds (LC-MS results of
one cycle of transformation have been included in Fig-
ure S23).[12] The dynamic frequency sweep (Figure S15)
indicated that the hydrogel exhibited dependence on the
frequency between 0.1 and 100 radsÀ1. The G’’ value (viscos-
ity) became closer to the G’ value (elasticity) at higher
frequencies. The G’ values were lower than 100 Pa within the
frequency range of 0.1–100 radsÀ1. These observations indi-
cated the presence of a weak gel. Biocompatible triggers for
the formation of hydrogels have recently attracted extensive
research interests.[13,14] The use of biocompatible VC to form
hydrogels might advance the application of molecular hydro-
gels in tissue engineering and controlled drug release.
nanofibers, which were longer than 5 mm, entangled each
other to form three dimensional (3D) networks for hydro-
gelation. We observed micelles between nanofibers in the gel
because of the presence of about 35% of unconverted
compound 1. The size of the micelles in the gel decreased to
about 25 nm. Upon the addition of H2O2 (0.1 wt%) to the gel,
the nanofibers were converted back to micelles (Figure S24).
These observations indicated that the propensity to self-
assemble and the nature of the self-assembled structures of
selenium-containing peptides could be controlled by the
redox trigger. Circular dichroism (CD) spectra (Figure S17)
indicated that compound 1 was present in a random-coil
conformation and that peptides in the gel formed by VC
adopted antiparallel b-sheet conformations.[15] Many peptides
with b-sheet conformations self-assemble into fibers and
gels.[13,16] However, we were unable to provide models to
explain the formation of micelles and fibers. Based on the
DLS results (Figure S18), the critical micelle concentration
(CMC) was 2.5 and 2.2 mgmLÀ1 for 1 and 2, respectively. It
was surprising that such a small difference in CMCs between
the two compounds led to such a huge difference in the nature
of the self-assembled nanostructures. Our system was similar
to biological systems that use kinase/phosphatase to regulate
their activity (a small difference in the chemical structure led
to a big difference in the properties).[17]
We also characterized compounds 1 and 2 by different
techniques. The reverse-phase HPLC results showed that
1 and 2 had retention times of 3.4 and 4.5 min, respectively,
thus indicating a change in the amphipathic property between
the oxidized and reduced forms (Figure S12A). The results
also indicated that the oxidized form (selenoxide) was more
hydrophilic than the reduced form (selenide). The ESI-MS
data (Figures S3 and S5) showed that the molecular ion peak
shifted from 976.2874 ([M+H]+) to 960.2915 ([M+H]+) as
a result of the reduction of 1 to 2, thus demonstrating the
existence of selenoxide and selenide structures. We also used
77Se NMR spectroscopy to investigate the conversion
between selenide and selenoxide. Compound 2, which con-
We then used transmission electron microscopy (TEM) to
characterize the morphology of self-assembled structures in
the solution and gel. Our observation of micelles with a size of
100–180 nm in the solution of compound 1 in PBS (Fig-
ure 2B) was consistent with the results obtained by dynamic
light scattering (DLS, Figure S19). Upon the addition of
1 equivalent of VC, the micelles gradually changed to nano-
fibers with a diameter of about 30 nm (Figure 2C). These
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tains selenide, showed a chemical shift of 285.71 ppm. After
the oxidation by H2O2, the chemical shift was 858.43 ppm,
thus indicating the conversion from selenide to selenoxide
(Figure S12B). We analyzed the change between the oxidized
form (selenoxide) and the reduced form (selenide) by X-ray
photoelectron spectroscopy (XPS). The binding energy of
Se 3d5 of compound 2 was 55.2 eV (Figure S12C), which was
similar to that of the selenide group. Compound 1 showed
a binding energy of 55.7 eV. Selenoxide-containing com-
pounds usually exhibited peaks around 57 eV.[18] The lower
binding energy of 1 was probably a result of the formation of
hydrogen bonds between selenoxide and peptides, which
might result in its disability to form supramolecular chains
and fibers.
Since the propensity to self-assemble and the nature of the
self-assembled nanostructures of selenium-containing pep-
tides could be tuned by the redox trigger, we planned to place
histidine-containing peptides on the surfaces of these nano-
structures and to demonstrate the possibility to switch their
hydrolysis activity. Our design and synthesis of compound 3
were comparable to that of 1 (Figure S25). Compound 3 bears
a histidine residue, which is the active site of esterase
enzymes. The reversible transformation between 3 and 4
could be achieved by redox control. This transformation leads
to a different density of histidine residues on the surface of
different kinds of nanostructures, resulting in the change in
hydrolysis activity.
Similar to the reversible conversion between compounds
1 and 2, the solution of compound 3 and gel of compounds 3
and 4 could also be switched by redox control (Figure 3A and
B, HEPES buffer, pH 7.4). We also observed the reversible
transformation between the micelles in solution and the
nanofibers in the gel (Figure 3A and B). Since 97.3% of 3 was
converted to 4, we did not observe micelles in the TEM image
of the gel after 24 hours. The higher conversion of 3 compared
with that of 1 suggested that the sequence of the peptide or
the morphology of the self-assembled structure might affect
the equilibrium. The redox process of compound 4 was
further investigated by cyclic voltammetry. Figure S31B
showed a reversible peak at 0.248 V and 0.188 V, correspond-
ing to the redox couple 3/4. The 60 mV difference between
the two peaks suggested a two-electron transfer between
selenide and selenoxide. Compared to the NADH/NAD
transformation in biological systems, which exhibited an
oxidation peak at 0.600 V (Figure S31A), the reversible
transformation between compounds 4 and 3 was more readily
achieved. The control peptide (AcFFYEGH) showed no
redox peak (Figure S31C).
Figure 3. TEM images of A) a solution of 3 in HEPES buffer, and
B) the gel resulting from treatment of this solution with VC (1 equiv;
image taken after 24 h treatment (the inserts show the solution and
gel, respectively). C) Absorbance (at 405 nm) upon the addition of
H2O2 (10 equiv) and VC (20 equiv after 13 min and another 20 equiv
after 19 min, control enzyme: peptide of Ac-YEGH). The absorbance
increase indicated the conversion from acetal-4-nitrophenol to 4-nitro-
phenol mediated by the catalyst. The changes in absorbance indicated
different catalyst activities. The assay was conducted in a two-phase
system with acetal-4-nitrophenol in dichloromethane and the peptides
in HEPES buffer, because the addition of high concentrations of H2O2
and VC to the aqueous solution of acetal-4-nitrophenol would have
resulted in absorbance increases. HEPES=2-[4-(2-hydroxyethyl)-1-
piperazinyl]ethanesulfonic acid.
be partially converted to micelles (89.2% of compound 3 after
13 min), leading to a rapid increase in absorption intensity
and a much higher catalytic activity (6–13 min in Figure 3C).
The higher catalytic activity of the micelles compared with
that of the fibers was probably due to the larger number of
histidine residues at the surface of the micelles and their
higher surface areas and mobility compared with those of
fibers (Compounds 3 and 4 were about 3.5 nm long. There-
fore, most of the histidine residues were buried in the inner
part of the nanofibers, which have a diameter of about 50 nm
and are longer than 5 mm, and micelles with a size of about 80–
150 nm). The hydrolysis activity could also be decreased by
the addition of VC (20 equiv after 13 min and another
20 equiv after 19 min; Figure 3C, 13–25 min). The rate, in
which the activity decreased when VC was added was smaller
than the rate, in which the activity increased, when H2O2 was
added, because the conversion induced by VC is slower than
that induced by H2O2 (94.5% and 97.1% of compound 3 after
19 and 25 min, respectively). Acetal-4-nitrophenol was not
The Kcat/KM values of the peptide for the hydrolysis of
acetal-4-nitrophenol to 4-nitrophenol were 10.5 and 1.1 for
the solution (micelles) and the gel (fibers), respectively
(Figure S30). The big difference in hydrolysis activity between
solution and gel suggested that the catalytic activity could be
switched by the redox trigger. The very slow increase in
absorption intensity during the first five minutes (Figure 3C)
indicated a slow rate of conversion from acetal-4-nitrophenol
to 4-nitrophenol and a low catalytic activity of the nanofibers
in the gel (97.3% of compound 3 in the gel). Upon the
addition of H2O2 (0.1 wt%, 10 equiv), the nanofibers would
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hydrolyzed in the HEPES buffer (control experiment) as
a result of the addition of H2O2 and VC. The control peptide
(AcYEGH) did not exhibit any switchable catalytic activity
because of the absence of selenium.
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We then used a simple cell-encapsulation experiment to
demonstrate the biocompatibility of the gelation process
catalyzed by VC. Mouse fibroblast 3T3 cells were first mixed
with a solution of compound 3 in Dulbeccoꢀs Modified
Eagleꢀs Medium (DMEM; final concentration = 2.5 wt%),
and 2 equivalents of VC were then added to trigger the
formation of cell–gel constructs within 5 minutes. The live/
dead assay showed that most of the cells (> 95%; Figure S32)
were alive, indicated by green dots in the cell–gel construct
2 hours after encapsulations. We also demonstrated the
esterase-like activity of fibers in live cells by incubating
smooth muscle cells (SMC) with fibers of compound 4
(0.1 wt%) for 1 hour. Recent results showed that self-
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and therefore used as carriers for hydrophobic anticancer
drugs to specifically deliver them into cancer cells.[19] We
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diacetate (FDA). FDA was widely used to test the activity
of esterase in cells, the higher fluorescence intensity in FDA-
treated cells with fibers compared with that in cells without
fibers suggested the esterase-like activity of the fibers within
the cells (Figures S33 and S34).
In summary, we reported the development of selenium-
containing peptides with the propensity to self-assemble. The
self-assembly of the nanostructures is reversible and can be
controlled by biocompatible redox triggers. The method of
using VC to trigger the formation of molecular hydrogels is
biocompatible and could be applied to the homogeneous
encapsulation of cells and therapeutic agents. There are many
reports about the enhanced activity of bioactive molecules,
such as antibacterial agents and artificial enzymes, by attach-
ing them to the surface of nanostructures.[20] Our system of
selenium-containing peptides with reversible transformations
between different kinds of nanostructures or between dis-
sociated and self-assembled stages could be used to switch
and control the activity of bioactive molecules. We believe
that this study will lead to the development of nature-
mimicking smart materials with promising properties.
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Received: April 16, 2013
Published online: && &&, &&&&
Keywords: hydrogels · peptides · redox chemistry · selenium ·
.
self-assembly
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