Nucleopeptide Assemblies Selectively Sequester ATP in Cancer Cells to Increase the Efficacy of Doxorubicin

Article abstract of DOI:10.1002/anie.201712834

Herein, we report that assemblies of nucleopeptides selectively sequester ATP in complex conditions (for example, serum and cytosol). We developed assemblies of nucleopeptides that selectively sequester ATP over ADP. Counteracting enzymes interconvert ATP

Full text of DOI:10.1002/anie.201712834

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Accepted Article
Title: Nucleopeptide Assemblies Selectively Sequester ATP in Cells
Authors: Huaimin Wang, Zhaoqianqi Feng, Yanan Qin, Jiaqing Wang,
and Bing Xu
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Nucleopeptide Assemblies Selectively Sequester ATP in Cells
Huaimin Wang,[a] Zhaoqianqi Feng,[a] Yanan Qin,[a] Jiaqing Wang,[a] and Bing Xu*[a]
Abstract: Here we report that assemblies of nucleopeptides
selectively sequestrate ATP in complex conditions (e.g., serum and
cytosol). We develop assemblies of nucleopeptides that selectively
sequester ATP over ADP. Counteracting enzymes interconvert ATP
and ADP to modulate the nanostructures formed by the
nucleopeptides and the nucleotides. The nucleopeptides,
sequestering ATP effectively in cells, slow down efflux pumps in
multidrug resistance cancer cells, thus boosting the efficacy of an
anticancer drug. Examining additional 11 nucleopeptides (including
D- and L-enantiomers) yields five more nucleopeptides that
differentiate ATP and ADP via either precipitation or gelation. As the
first example of using assemblies of nucleopeptides for interacting
with ATP and disrupting intracellular ATP dynamics, this work
illustrates the use of supramolecular assemblies to interact with
small and essential biological molecules for controlling cell behaviors.
including
as
antibiotics,[14]
hydrogelators,[15]
molecular
recognition,[16] and promoters for cell uptake of nucleic acids,[17]
and protease resistant peptide derivatives to accelerate the
degradation of certain peptide nanofibrils.[18] Most importantly,
bearing
nucleobase(s),
nucleopeptides
would
exhibit
appreciable affinity to adenosine on ATP even under
physiological condition due to the well-known Watson-Crick
base pairs in the context of cells and in developing
supramolecular materials.[19]
Adenosine triphosphate (ATP), one of the most important
biological anions, plays crucial roles in many cellular processes,
including cellular respiration,[1] energy transduction,[2] enzyme
catalysis,[3] and signaling.[4] Therefore, selective binding or
sequestration of these polyphosphate species under biological
conditions would help elucidate their roles in relevant
physiological events and provide a powerful way to control
cellular processes. Much efforts have focused on developing
specific receptors, such as synthetic host-guest receptors,[5]
DNA[6] and RNA-aptamers,[7] bis-Zn based artificial receptors,[8]
recombinant proteins and synthetic peptides,[9] for recognizing
ATP. Among these strategies, protein engineering or peptide
fragment mimetic is a direct approach for ATP recognition or
sequestration.[9a, 9b] Although some of them exhibit high affinity
10]
toward ATP in water[9c,
or phosphate-free buffers (e.g.,
HEPES[8a, 11]), these synthetic molecules are largely ineffective
for recognizing ATP in complex physiological conditions (i.e.,
PBS, human serum, and mammalian cells). Therefore, the
development of molecules for selectively sequestering ATP in
complex medium is still limited, and their applications in cells
remain unexplored. We have found that a nonapeptide formed a
hydrogel instantly upon the addition of ATP.[12] This rather
unexpected observation indicates that it is feasible to use
assemblies of small molecules to interact with ATP. To increase
the specificity towards ATP, we decided to explore the use of
supramolecular assemblies of nucleopeptides for selectively
sequestering ATP in complex physiological conditions.
Figure 1. (A) Structure of a nucleopeptide (NP1) to sequester ATP selectively.
(B) Illustration of assemblies of NP1 interaction with ATP or ADP and the
reversible phase transition of the assemblies controlled by
a pair of
counteracting enzymes. (C) Plausible mechanism of assemblies of NP1 in a
multidrug resistance cell to sequestrate ATP, thus slowing down drug efflux
and boosting drug efficacy.
In the work, nucleopeptide refers the peptides conjugated with
nucleobase(s) at the N-terminal of a peptide, a type of peptidic
derivatives that receives less investigation.[15a, 20] To explore the
possibility of using nucleopeptides for selectively sequestering
ATP, we introduced thymine to cap the N-terminal of
a
Nucleopeptides, as the covalent conjugates of nucleobases
and peptides,[13] exhibit excellent biocompatibility, good
biostability, facile functionality, readily self-assemble in water,
and promise useful biological and biomedical applications,
nonapeptide that instantly formed a hydrogel upon the addition
of ATP.[21] Our study shows that the assemblies (rather than
monomers) of a nucleopeptide (NP1) (Figure 1A) selectively
sequester ATP over ADP in complex physiological conditions,
evidenced by phase transition. Hexokinase (HK)[22] and creatine
phosphokinase (CPK)[23] are able to control the cycle of
ATP/ADP, thus modulating phase transition (from precipitate to
solution and vice versa) and reversibly changing the
morphologies of assemblies of NP1 and the nucleotides in PBS
(Figure 1B). Most importantly, NP1 exhibits selectivity towards
ATP under physiological conditions, including in serum and in
cells. Being incubated with multiple drug resistance cancer cells,
NP1 slows down the efflux of an anticancer drug (e.g.,
doxorubicin (Dox)), results in long cellular retention of Dox, thus
[a]
Dr. H. Wang, Ms. Z. Feng, Ms. Y. Qin, Dr. J. Wang and Prof. Dr. B.
Xu
Department of chemistry
Brandeis University
415 South St, Waltham, MA 02454, USA
Fax: (+) 1-781-736-2516
E-mail: bxu@brandeis.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201712834
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boosting the anticancer activity of Dox against Dox-resistance
cancer cells (Figure 1C). Examining 11 analogs of NP1 identifies
five more nucleopeptides that differentiate ATP and ADP via
either precipitation or gelation. As the first use of assemblies of
small molecules for selectively sequestering ATP, this work
opens up a new approach for rationally design supramolecular
assemblies for sequestering (or recognizing) small biological
molecules in complex physiological conditions to mimic the
functions of proteins and to control cell behaviors.
of NP1 to 50%, and adding ADP slightly decreases the α-helix of
NP1 to 40%. The red shift of two negative peaks of 200 nm and
223 nm in the presence of ATP (or ADP) agrees with that ATP
or ADP enhances the assemblies of NP1. Addition of more
molar ratio of ATP (or ADP) results in the decrease of CD signal
(Figure S3). When its equivalent increases, ATP causes more
decrease of the CD signals than ADP does, indicating
assemblies of nucleopeptide interact strongly with ATP and also
agreeing with more precipitates generated by increasing the
amount of ATP. The slight changes of NP1 conformation after
addition of ATP and ADP, suggesting stable assemblies of NP1
play crucial role for sequestering ATP. At 0.05 wt%, NP1 (Figure
2E) exhibits dominantly unordered structures (55%). The
presence of ATP or ADP slightly reduces the portion of
unordered structures, but significantly increases the percentage
of α-helix from 0% to 9.5% or 15.0%, respectively. While the CD
spectra of NP1 and the mixture of NP1 and ADP indicates slight
contribution of linear dichroism, little linear dichroism contributes
to the CD of the mixture of NP1 and ATP (Figure S4). These
results agree with the strong interaction of NP1 and ATP. Static
light scattering (SLS) of NP1 hardly changes until the
concentration of NP1 is above 0.2 wt% (Figure S5), suggesting
that NP1 starts assemble to form detectable nanofibers at the
concentrations higher than 0.2 wt%. These results indicate that
(i) the assemblies of NP1 interact stronger with ATP or ADP
than the monomer of the NP1 does; (ii) ATP or ADP affects the
secondary structure of NP1, thus resulting in different
assemblies (Figure 1). Most importantly, these results confirm
that NP1 interacts with ATP and ADP differently in PBS buffer.
Figure 2. TEM images of NP1 (0.4 wt%) in PBS buffer (pH7.4) (A) without or (B,
C) with 1 equiv. of (B) ATP and (C) ADP. Insets: the corresponding optical
images. Scale bar is 50 nm. CD spectra of NP1 at (D) 0.4 wt% and (E) 0.05 wt%
with or without ATP or ADP (equal molar with NP1).
We designed nucleopeptide NP1 (Figure 1A) according to the
following rationale: (i) a D-nonapeptide, ffkkfklkl, consists of ff for
increasing self-assembly ability, kkfklkl for interacting with
phosphate group on ATP,[12] and D-amino acids (f = D-
phenylalanine, k = D-lysine, and l = D-leucine) for proteolytic
resistance; (ii) thymine, capping the N-terminal of nonapeptide,
ensures affinity to adenosine on ATP. After obtaining NP1 by
solid phase peptide synthesis (SPPS),[24] we first examined the
ability of NP1 for differentiating ATP and ADP in PBS buffer.
NP1 forms a clear solution, which becomes precipitates after the
addition of ATP (Figure 2). But NP1 remains as a transparent
solution in the presence of ADP. As revealed by transmission
electron microscopy (TEM), NP1 forms short nanofibers with
length of 40±5 nm and width of 4±2 nm, which, in the presence
of ATP, turn into uniform nanofibers with several hundred
nanometers in length and 7±2 nm in width, which likely further
aggregates to precipitate. ADP interacting with NP1 only results
in short nanofibers with diameter of 5±2 nm, which remains
soluble. Moreover, NP1 differentiates ATP and ADP in human
serum (i.e., ATP interact with NP1 to form precipitates in serum,
but NP1 remains soluble in serum upon the addition of ADP
(Figure S1)), suggesting that the designed nucleopeptides
should function under complex physiological conditions.
Figure 3. NP1 assemblies with ATP in the presence of glucose (A) without or
(B) with addition of HK. NP1 assemblies with ADP in the presence of Pcr (C)
without or (D) with the addition of CPK. Insets are the corresponding optical
images. The concentration of NP1 is 0.4 wt%, equal molar ATP or ADP is
added. All experiments are performed in 100 mM PBS buffer, pH7.4 for 24 h.
Scale bar in (A) to (D) is 100 nm.
To further examine the ability of NP1 to differentiate ATP and
ADP in the presence of other biological molecules (e.g.,
metabolites and enzymes), we employed a pair of counteracting
enzymes to interconvert ATP and ADP for controlling the self-
assembly of NP1. The pair of enzymes are hexokinase (HK),
which phosphorylates hexoses and generates ADP by
transferring the phosphate group from ATP to glucose, and
creatine phosphokinase (CPK), which catalyzes the generation
As revealed by the circular dichroism (CD) spectra and the
analysis of the CD by DichroWeb,[25] NP1, at 0.4 wt%, presents
predominantly in α-helical conformation (45%) with 28% of β-
sheet and 19% of unordered structures (Figure 2D, Figure S2).
Adding ATP slightly increases the α-helix conformation content
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of ATP from ADP in the presence of phosphocreatine (Pcr). With
glucose, NP1 plus ATP remains as a precipitate, though TEM
reveals more bundles of nanofibers with the fibril diameters of
8±2 nm (Figure 3A). Adding HK hydrolyzes ATP to ADP, which
enhancing the anticancer efficiency of Dox, agreeing with that
the assemblies of NP1 sequester ATP in vitro (Figure S5).
We also used TEM to image live cells incubated without or
with NP1. The cells incubated with NP1 exhibits nanofibrous
structures having diameters of 7±2 nm, which are similar with
the TEM image of the cell free experiment (Figures 5A and S12).
To test the influence of NP1 on the ATP metabolism in live cells,
we chose 10 µM of Dox to treat MES-SA/dx5 cells to increase
the measurable signal without immediately causing cell death.
Then, we measured the cellular ATP levels in Dox untreated or
treated conditions in the presence of NP1. The cells maintain
ATP levels after the treatment of NP1 within 5 h, while the
control cells increase the ATP levels (Figure 5B). Because NP1
exhibit little cytotoxicity, this result suggests that NP1 affects the
metabolic processes of ATP. To further demonstrate the
interaction between NP1 and ATP inside cells, we synthesized
NBD labelled NP1 (NP1-NBD) as a structural analog of NP1,
which retained ability for sequestering ATP (Figure S13). CLSM
images (Figures 5C and S14) indicate that almost all ATP
overlapped with NP1-NBD, and the fluorescence of ATP hardly
changes with time (Figure S15). These results together further
confirm the designed nucleopeptide selectively sequesters ATP
to boost anticancer drug activity in MDR cells.
turns the precipitates into
a clear solution and the long
nanofibers into short (20-100 nm) and thin (4±2 nm) fibers
(Figure 3B). With Pcr, NP1 plus ADP remains as a clear
solution, containing short nanofibers of 3±2 nm in width (Figure
3C). The addition of CPK to the solution turns ADP into ATP and
the solution into precipitates, which consist of long nanofibers
with the diameters of 11±2 nm (Figure 3D). These results
indicate that NP1 is able to sequester ATP when ATP forms via
cellular metabolism.
Figure 4. (A) CLSM images show the inhibition of Dox efflux by NP1 in MES-
SA/dx5 cells at 0 h (changing to fresh medium without Dox after washing 3
times) and 5 h (further incubation after changing medium). Scale bar is 20 µm.
(B) MES-SA/dx5 cell viability that treated with Dox, NP1 or the mixture of NP1
and Dox (5 µM) for 48 h (n=3, ***: p < 0.001). Bars shown are mean ± SEM.
Expression of ATP-dependent efflux pumps in cancer cells
plays a crucial role in multiple drug resistance (MDR).[26]
Moreover, the concentration of ATP is usually several millimolar
in human cells.[27] 31P NMR spectra indicated that NP1 can slow
down the hydrolysis rate of ATP by ALP (Figure S7). Therefore,
we tested the ability of NP1 for sequestering ATP in MDR
cancer cells. After confirming that NP1 selectively sequester
ATP in the buffer containing cellular major components (e.g.,
various proteins and glycans) (Figure S8), we treated MES-
SA/dx5 cells[28] with NP1 in the presence of Dox. Five hours after
changing to the medium from with to without Dox, most of Dox
remains inside the MES-SA/dx5 cells treated with NP1. But
there is little Dox in the MES-SA/dx5 cells without NP1 treatment
(Figures 4A and S9). These results suggest that the assemblies
of NP1 likely sequester ATP inside cells, thus preventing the
efflux of Dox by the efflux pump driven by ATP. It is possible that
the assemblies of NP1 to interact with molecules other than ATP
to contribute to the retention of Dox inside the cells. We further
evaluated anti-proliferation efficiency of Dox in combination of
NP1 against MES-SA/dx5 cells. Exhibiting little cytotoxicity by
itself, NP1, significantly increases the cytotoxicity of Dox against
MES-SA/dx5 cells in a dose-dependent manner (Figures 4B,
S10 and S11). Specifically, the addition of NP1 at the
concentration of 500 µM (or 200 µM) increases the cell death
caused by Dox from 46% to 92% (or 67%) (Figures 4B and
S10). Moreover, NP1 exhibits dose-dependent effect in
Figure 5. (A) TEM images of cell components collected from live cells without
(control) or with the incubation of NP1 for 5h. Scale bar is 100 nm. (B) ATP
concentrations in the live cells incubated with NP1 (500 µM), NP1 plus Dox
(10 µM), Dox (10 µM), and culture medium (n = 3, the asterisks indicate the
difference between 1 h with 3 or 5 h. ns: non-significant, *: p < 0.05, **: p <
0.01). Bars shown are mean ± SEM. (C) CLSM images of MES-SA/dx5 cells
incubated with Alexa-ATP and NP1-NBD (50 µM). Scale bar is 5 µm.
To correlate the structures of nucleopeptides with the ability of
sequestering ATP, we synthesized 11 analogues of NP1 and
tested their phase transition in the presence of ATP or ADP
(Scheme S2 and S3, Table S2). NP2, as an L-enantiomer of
NP1, which becomes precipitates after the addition of ATP, but
remains as a transparent solution in the presence of ADP
(Figure S16). TEM reveals that the amorphous nanostructures
formed by NP2, transform into spherical like structures after
addition of ATP with width of 29 ±2 nm, which further interact
with each other to form 3D network (Figure S16) and precipitate
from the solution. On the contrary, ADP interacts with NP2 to
results in nanofibrous structure with width of 10±2 nm. Different
morphologies of the nanostructures resulted from the solutions
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Keywords: self-assembly • nucleopeptide • enzyme switch •
targeting metabolism • hydrogel
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10.1002/anie.201712834
Angewandte Chemie International Edition
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