Highly Selective Binding and Inhibition of Pyr-His-Pro-NH2 (TRH) Function using a Polypyridinyl Macrocyclic Receptor with an Amphiphilic Cavity

Article abstract of DOI:10.1002/chem.202000888

Macrocycle, cyclo[4] [(1,3-(4,6)-dimethylbezene)[4](2,6-(3,5)-dimethylpyridine (B4P4), shows highly selective binding affinity with protirelin (Pyr-His-Pro-NH₂; TRH) among the tested 26 drug or drug adductive substrates. The stable complexation in a 1:1 manner was fully characterized in solution, gas phase, and solid state study. Furthermore, B4P4 acts as an efficient TRH inhibitor even at [macrocycle]:[drug] <1:300, both in membrane transport and cellar incubation. The current work provides an unprecedented strategy for macrocycles to be efficiently used in drug target therapy.

Full text of DOI:10.1002/chem.202000888

Accepted Article
Accepted Article
Title: Highly Selective Binding and Inhibition of Pyr-His-Pro-NH2 (TRH)
Function using a Polypyridinyl Macrocyclic Receptor with an
Amphiphilic Cavity
Authors: Chao-Ping Hou, Jian Yang, Lei Zhang, Zhen-Hua Ma, Qian Li,
Jun-Feng Xiang, and Han-Yuan Gong
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202000888
Link to VoR: https://doi.org/10.1002/chem.202000888
01/2020

10.1002/chem.202000888
Chemistry - A European Journal
COMMUNICATION
Highly Selective Binding and Inhibition of Pyr-His-Pro-NH2 (TRH)
Function using a Polypyridinyl Macrocyclic Receptor with an
Amphiphilic Cavity
Chao-Ping Hou,[a] Jian Yang,[a] Lei Zhang,[b] Zhen-Hua Ma,[a] Qian Li,[c,d] Jun-Feng Xiang,[c,d] Han-Yuan
Gong*[a]
[a]
Chao-Ping Hou, Jian Yang, Zhen-Hua, Han-Yuan Gong
College of Chemistry
Beijing Normal University
No. 19, Xinjiekouwai Street, Beijing, 100875, P. R. China
E-mail: hanyuangong@bnu.edu.cn
[b]
[c]
[b]
Lei Zhang
Chongqing Customs Technical Center
No. 8 Honghuang Road, Jiangbei District, Chongqing, 400020, P. R. China
Qian Li, Jun-Feng Xiang
Beijing National Laboratory for Molecular Sciences
Zhongguancunbeiyijie 2, Beijing, 100190, P. R. China
Qian Li, Jun-Feng Xiang
University of Chinese Academy of Sciences
Beijing, 100049, P. R. China
Supporting information for this article is given via a link at the end of the document.
Abstract: Macrocycle, cyclo[4] [(1,3-(4,6)-dimethybezene)[4](2,6-
(3,5)-dimethypyridine (B4P4), shows highly selective binding affinity
with protirelin (Pyr-His-Pro-NH2; TRH) among tested 26 drug or drug
adductive substrates. The stable complexation with a 1:1 manner
was fully characterized in solution, gas phase, also solid state study.
Furthermore, B4P4 acts as efficient TRH inhibitor even
[macrocycle]:[drug] < 1:300, both in membrane transport and cellar
incubation. Current works provide an unprecedented strategy of
macrocycle to efficient participate in drug target therapy.
specific drug inhibitor is still considered with potential benefit for
target therapy. As a typical example, protirelin (Pyr-His-Pro-NH2;
TRH) is a drug mainly used to assist in the diagnosis of Graves'
disease and to identify and diagnose lesion sites associated with
hypothyroidism. However, TRH inhibition is of significance in the
disease treatment since excessive TRH may cause unpleasant
side effects in respiratory, nervous, cardiovascular and digestive
systems.8 Here we report an artificial polypyridinyl macrocycle
with
an
amphiphilic
cavity,
cyclo
[4]
[(1,3-(4,6)-
dimethylbezene)[4](2,6-(3,5)-dimethylpyridine (B4P4), which
forms a thermodynamically and kinetically stable complex with
TRH and does so with selectivity over 26 other tested drug or
drug adducts. This conclusion is supported by standard 1H NMR
and temperature dependent 1H NMR spectroscopic studies, one-
dimensional nuclear Överhauser effect (1D NOE) analyses, UV-
vis spectral studies, electrospray ionization high resolution mass
spectral (ESI-HRMS), single crystal X-ray diffraction results and
theoretical calculation analysis. Further study proved slight
amount (≤ 2% molar equiv.) of the macrocycle can inhibit TRH
with unusual high efficiency in membrane transport9, also PC12
cell incubation10 (Scheme 1).
The identification, binding, release, and activity of specific
drugs is of great significance for medicinal chemistry and clinical
practice alike.1 The first patent detailing the use of cyclodextrin
for pharmaceutical issued in 1953.2 Since then, interactions
between macrocyclic receptors and drug and drug candidates
via non-covalent interactions has been extensively explored as a
means to improve the inherent features of physiologically
substrates. Macrocyclic receptors considered in this context
include cyclodextrins, crown ethers, calixarenes, cucurbituris,
and pillararenes, among others.3 These receptors can act as
drug carriers to promote drug transport and, in idealized cases,
achieve precise targeted therapy treatment of specific diseases,
such as inflammation, bacterial infections, cancer, virosis,
malarial, epileptic disorder, genetic deficiencies, Alzheimer's
disease, tuberculosis, etc.4 Benefits of receptor-mediated
formulations include improvements in drug solubility, stability,
and bioavailability.5 Furthermore, some reports have involved
the use of artificial macrocycles with specific inherent
bioactivity.6
Surprisingly, to our knowledge, macrocyclic drug inhibitors
have been much less well developed. However, there are limited
reports of cucurbit[n]urils being used to reduce the toxicity of
nitidine chloride and camptothecin, or work as small-molecule
kinase inhibitors.7 Developing artificial macrocyclic receptor for
Scheme 1. Cyclo[4][(1,3-(4,6)-dimethylbenzene)[4](2,6-(3,5)-dimethylpyridine
(B4P4), a new receptor with highly selective TRH binding that (I) acts as a
TRH inhibitor both in membrane transport (II) and cell proliferation studies (III).
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Scheme 2. Synthesis of macrocycle B4P4 (a). Top (b1, c1) and side (b2, c2) views of near circular and oral conformations of B4P4 shown in B4P4•5dioxane and
B4P4•acetonitrile•0.5dioxane, respectively. Note: Four pyridine nitrogen atoms on the macrocycle pointing to the same side of the cavity (b2) and (c2) in both
cases. The amphiphilic property of B4P4 cavity was shown in single crystal structure of [B4P4•2toluene•4.5H2O] and [B4P4•4THF•4H2O] in top view (d1, e1) and
side view (d2, e2), respectively. All the other atoms and solvent molecules have been omitted for clarity.
As shown in Scheme 2a, B4P4 was obtained with 25%
cyclization yield via a fragment coupling strategy. Only one set
of high resolution signals of B4P4 with similar narrow width was
observed in temperature dependent 1H NMR in N,N-
dimethylformamide-d7 (DMF-d7) from 213 K to 393 K. This was
taken as an evidence that the skeleton of macrocycle is flexible
and subject to fast conformational flipping over a wide range of
temperatures. This inference is supported by 1D NOE and
NOESY spectral studies carried out at 298 K in DMSO-d6; here,
correlations between H(c) and H(d) were observed, again
presumably due to the fast flipping that serves to shorten these
average interatomic distance to values (less than 6 Å) below
what might otherwise be expected (cf. Supporting Information
(S17-18)).
possible integrated intermolecular hydrogen bonding and/or π-π
donor acceptor interactions. Toward this end, we tested a range
of drug and drug-like species, including 10 peptides, 5 amino
acids, 11 carbohydrates, using a combination of 1H NMR and
UV-vis spectroscopies in DMSO-d6 or DMSO (cf. S26).
1H NMR and UV-vis spectroscopic studies were carried out
to explore the interaction between B4P4 and each substrate in
DMSO-d6 or DMSO (cf. S27-S54). B4P4 only has obvious
response with TRH among all the 26 tested substrates. Further
1H NMR Job plot study with maximum value of ([H]/([H]+[G])) as
0.5 was consistent with an 1:1 (H/G) binding stoichiometry (cf.
S57).
The association constant (Ka) between B4P4 and TRH was
detected in DMSO/water (1:9, v/v), and the values of logKa were
obtained as 3.8(2) or 4.1(2) via UV-vis titrations or isothermal
titration calorimetry (ITC) experiment, respectively. Relative
binding thermodynamic parameters at 298 K were also obtained
from ITC. The results, namely ΔGө = -24(1) kJ•mol-1; ΔHө =
3.3(2) kJ•mol-1; and ΔSө = 90(3) J•mol-1 •K-1, deduced that
entropy effect should be the main driving force during the
complexation. It was considered due to the change of solvent
shell effect in the process (cf. S59-61).
The flexibility of B4P4 was further proved via single crystal X-
ray diffraction analysis (Scheme 2b1, 2b2, 2c1, 2c2). Near circular
and oval cavities of B4P4 were observed in the single crystals of
B4P4•5dioxane and B4P4•acetonitrile•0.5dioxane, respectively.
Four pyridine nitrogen atoms on the macrocycle point to the
same side of the cavity in both cases. The finding implies the
pyridine moieties can cooperate for the guest binding. (cf. S20-
S23).
Furthermore, single crystal X-ray diffraction study
characterized the amphiphilic cavity of B4P4. In both cases of
[B4P4•2toluene•4.5H2O] and [B4P4•4THF•4H2O], the pyridinyl
pointing side of macrocyclic cavity is hydrophilic to stabilize the
cluster of four water molecules. Another side shows oleophilic
property and bind with organic molecules (e.g., toluene or THF)
(cf. Scheme 2d1, 2d2, 2e1, 2e2 and S24-S25).
Additional support for proposed formation of 1:1
supramolecular complex [B4P4•TRH] came from ESI-HRMS
with the signal corresponding to [B4P4 + TRH + H]+• (m/z calc.
1199.6599; found. 1199.6346) (cf. S64).
The dynamic stability of the complex between B4P4 and
TRH was further proved via temperature dependent 1H NMR
from 213 K to 393 K. At each detected temperature, the
linewidth of H(c) on B4P4 expands with increasing [TRH] from 0
to 10 molar equiv. The finding indicated that the conformation
inversion rate of B4P4 in [B4P4•TRH] is slower than free B4P4
(cf. S63).
The large open cavity present in B4P4, coupled with the
amphiphilicity inferred on the basis of the X-ray diffraction
analyses, led us to consider that it might act as a molecular
receptor capable of binding small, multifunctional molecules
(e.g., small drugs or their derivatives) via a combination of
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UV-vis spectroscopic study in DMSO showed a charge
transfer (CT) absorption band appeared at long wavelength (≥
310 nm) in the mixture containing B4P4 and TRH,
corresponding to their π-π donor-acceptor interaction (cf. S58).
These findings in 1D NOE spectra of the mixture suggested that
TRH binds the macrocycle with inclusion mode via
intermolecular hydrogen bonding and π-π donor-acceptor
interactions (cf. S56). The proposed 1:1 inclusion binding mode
of [B4P4 • TRH] was further proved via single crystal X-ray
diffraction study (Figure 1a, 1b).11 On the basis of the 1D-NOE
and single crystal X-ray diffraction data, the theory calculation
was further carried out using MMFF force field via Discovery
Studio software package for deeper insight into the binding
between the macrocycle and TRH both in vacuum and water
solution. In optimized simulated complex structures, the nitrogen
atoms of pyridine units on the B4P4 act as acceptors to form
intermolecular hydrogen bonds with the NH group of Pyr
residual moity on TRH. Furthermore, π-π donor-acceptor
interactions between the neighbour pyridinyl ring on the B4P4
and pyr moity of TRH is also characterized with short distance (≤
3.8 Å) (cf. S65-68).
expanded half width of TRH 13C signals, which were correspond
to chemical shift difference and slower exchange speed between
TRH outside and inside of the vesicles (Figure 2b3). Surprisingly,
with the presence of vesicles, B4P4 (0.003 molar equiv.) as
adductive reduce the expansion of signal half width, also cause
up field chemical shift change (Figure 2b4; similar as 2b2) of the
signals (i.e. α and β) corresponded to TRH. These finding
implied that B4P4 act as an inhibitor for TRH transport through
the vesicle membrane (Table 1 and Figure 2). It was suggested
that the formation of [B4P4•TRH] on phospholipid bilayer inhibit
TRH passive diffusion through the membrane. Half an hour,
adding B4P4 and TRH with different sequences in the
membrane transport were carried out. First addition of B4P4 or
TRH induce the results (Figure2b5 and 2b6) similar as the cases
with the absence and presence B4P4 (Figure2b3 and 2b4). The
finding indicates that the TRH passive diffusion mechanism is
corresponding to [B4P4•TRH] rather than simple B4P4. And the
mechanism is possible reason to induces the unprecedented
efficiency of the TRH inhibition shown in this example, namely
slight amount of B4P4 (0.003 molar equiv.) can prevent much
excess TRH through the membrane.
Table 1. The condition of 13C-labeled TRH membrane transport experiments.
Buffer
solution[a]
entry
LUVs
EuCl3
TRH[b]
DMF-d7
B4P4[c]
b1
b2
√
√
_
_
_
_
_
_
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
_
√
_
_
_
_
√
_
√
√
√
b3
Figure 1. Molecular model of the complex [B4P4•TRH] in water solution (0.02
mM). Top (a) and side (b) views of the monomeric complex of B4P4•TRH.
The hydrogen atoms and solvent water molecules are omitted for clarity,
b4
b5[d]
b6[e]
To deeper insight the binding pattern between B4P4 and
TRH, the binding affinity of B4P4 and a serious of other
substrates was used for comparative analysis. These substrates
included drug guests with: (1) “Pro” (C-term) residual group with
amide form (i.e., meropenem, L- prolinamide, Boc-His-Pro-NH2);
(2) “His” moiety (i.e., Boc-His-Pro-NH2, lutrelin); and/or (3) “Pyr”
(N-term) residual part (i.e., fasoracetam, BPP 9A, fertirelin).
B4P4 has no response with all these guests. The results implied
that the interaction between the macrocycle and TRH is not
simply on specific residue or fragment effect(s). The affinity of
TRH towards B4P4 is suggested that TRH structure folding fits
well with the cavity of B4P4 (cf. S55).
Note: “√” represents the system contains the component. And “_“represents
the absence of the corresponding material(s). [a] HEPES-buffer D2O (pD 6.5).
[b] 13C-labeled TRH. [c] DMF-d7 solution of B4P4. [d] Adding 13C-labeled TRH
at first, and then adding DMF-d7 solution of B4P4 half an hour later. [e] Adding
DMF-d7 solution of B4P4 at first, and then adding TRH half an hour later.
Highly selective TRH recognition of B4P4 led us to consider
its further biological application. TRH membrane transport
experiment was first carried out as a model in the absence or
presence of B4P4. Herein, 13C-labeled NMR method was used
to characterize TRH transportation. The large unilamellar
vesicles (LUVs) solution was prepared in HEPES-buffered D2O
(pD 6.5) (500 uL), and then DMF-d7 solution of B4P4 (5 mM, 15
uL), 13C-labeled TRH (50 mM) and the chemical shift reagent
EuCl3 (300 mM) were added. Little if any response was seen
with adding small amount of B4P4 (0.003 molar equiv.) in the
absence of vesicles (Figure 2b2). Additional LUVs induced
Figure 2. (a) Scheme represent of possible TRH passive diffusion prohibition
mechanism via the complex [B4P4•TRH] inserting into phospholipid bilayer. *
shown the 13C-labled carbon atoms on TRH. (b) The expanded 13C NMR
spectra of TRH shown in 13C-labeled membrane transport experiments listed
in Table 1.
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The effect of B4P4 on the antiproliferative activity of TRH
used in conjunction with Aβ25-35 tested in PC12 cells was
investigated (in Figure 3). PC12 cells were pretreated with Aβ25-35
for 24h in advance, then incubated with different concentrations
(i.e., 0, 10, 50, 100 and 500 μM) of TRH in the absence or
presence of 10 μM B4P4 for 48h. Cell viability was determined
by CCK-8 assay. The results are shown in Figure 3. The viability
of Aβ25-35 induced PC12 cells increased with increasing [TRH] in
the absence of B4P4. On the other hand the cell viability trend
was reversed, and reverted to basal levels, when TRH was
tested in conjunction with B4P4. The effect was manifest even
when even [macrocycle]:[drug] = 1:50 on a per mole basis.
We are grateful to the National Natural Science Foundation of
China (21672025, 21971022 and 21472014), National Basic
Research Program of China (973 Program 2015CB856502), the
Young One Thousand-Talents Scheme, the Fundamental
Research Funds for the Central Universities, and the Beijing
Municipal Commission of Education for financial support.
Keywords: Macrocyclic receptor • molecular recognition • drug
Inhibition • slight adductive dosage
[1]
[2]
[3]
I. Ekladious, Y. L. Colson, M. W. Grinstaff, Nat. Rev. Drug Discovery.
2019, 18, 273.
K. Freudenberg, F. Cramer, H. Plieninger, Deutsches Patentamt.
895769, Nov 5, 1953.
(a) Y. Lu, Q. Hu, Y. Lin, D. B. Pacardo, C. Wang, W. Sun, F. S. Ligler,
M. D. Dickey, Z. Gu, Nat. Commun. 2015, 6, 10066. (b) E. S. Español,
M. M. Villamil, Biomolecules 2019, 9, 90. (c) K. M. Park, M. Y. Hur, S. K.
Ghosh, D. R. Boraste, S. Kim, K. Kim, Chem. Commun. 2019, 55,
10654. (d) X.-B. Hu, Z. Chen, L. Chen, L. Zhang, J.-L. Hou, Z.-T. Li,
Chem. Commun. 2012, 48, 10999. (e) S.-K. Ko, S. K. Kim. A. Share, V.
M. Lynch, J. Park, W. Namkung, W. V. Rossom, N. Busschaert, P. A.
Gale, J. L. Sessler, I. Shin, Nat. Chem. 2014, 6, 885. (f) G. Yu, W. Yu,
Z. M, C. Gao, F. Huang, small 2015, 11, 919. (g) L. Shangguan, Q.
Chen, B. Shi, F. Huang, Chem. Commun. 2017, 53, 9749.
[4]
(a) G. Granata, I. Paterniti, C. Geraci, F. Cunsolo, E. Esposito, M.
Cordaro, A. R. Blanco, S. Cuzzocrea, G. M. L. Consoli, Mol.
Pharmaceutics. 2017, 14, 1610. (b) L. Gao, M. Li, S. Ehrmann, Z. Tu, R.
Haag, Angew. Chem. Int. Ed. 2019, 58, 3645; Angew. Chem. 2019, 131,
3684. (c) G. Lan, K. Ni, W. Lin, Coord. Chem.Rev. 2019, 379, 65. (d) S.
Mallick, K. Pal, F. Chandra, A. L. Koner, Phys. Chem. Chem. Phys.
2016, 18, 30520. (e) L. Gallego-Yerga, J. M. Benito, L. Blanco-
Fernández, M. Martínez-Negro, I. Vélaz, E. Aicart, E. Junquera, C. O.
Mellet, C. T. de Ilarduya, J. M. G. Fernández, Chem. Eur. J. 2018, 24,
3825. (f) V. Oliveri, G. Vecchio, Chem. Asian J. 2016, 11, 1648. (g) S.
Li, J. Y.-W. Chan, Y. Li, D. Bardelang, J. Zheng, W. W. Yew, D. P.-C.
Chan, S. M. Y. Lee, R. Wang, Org. Biomol. Chem. 2016, 14, 7563. (h)
Z. Qin, D.-S. Guo, X.-N. Gao, Y. Liu, Soft Matter. 2014, 10, 2253.
J. Zhou, G. Yu, F. Huang, Chem. Soc. Rev. 2017, 46, 7021.
X. Wu, Y. Chen, Q. Yu, F.-Q. Li, Y. Liu, Chem. Commun. 2019, 55,
4343.
Figure 3. TRH inhibition property of B4P4 corresponding with viability of Aβ25-
induced PC12 cells. The experiments were repeated in 3 independent
35
experiments. *p < 0.01, in comparison with Aβ25-35 treatment cells.
Further controlled experiments were carried out. In both
cases, B4P4 and TRH were separately added with 24 hours
interval for the cellar incubation (cf. S73). Compared with the
result with adding macrocycle and TRH at the same time, the
inhibition effects were less in both separated addition
procedures. The results implied that B4P4 takes effect as TRH
inhibitor in living cells, possible with the complex form [B4P4•
TRH]. It is suggested that B4P4 can inserted into vesicles or cell
surfaces, to form complex [B4P4 • TRH], which inhibits the
passive diffusion of TRH. The competition and/or interaction
between [B4P4•TRH] and TRH receptors on the cell surface are
also possible factors to induce the cell experiment results.
[5]
[6]
[7]
(a) W. Li, H, Yin, D. Bardelang, J. Xiao, Y. Zheng, R. Wang, Food
Chem Toxicol. 2017, 109, 923. (b) X. Yang, Z. Wang, Y. Niu, X. Chen,
S. M. Y. Lee, R. Wang, Med. Chem. Commun. 2016, 7, 1392. (c) X.
Yang, Q. Huang, D. Bardelang, C. Wang, S. M. Y. Lee, R. Wang, Org.
Biomol. Chem. 2017, 15, 8046.
In summary, we have found that B4P4 represents a flexible
receptor with an open amphiphilic cavity. It binds with good
kinetic and thermodynamic stability protirelin (Pyr-His-Pro-NH2,
TRH) and does so selectively over 26 other potential substrates.
Membrane transport experiments and celluar activity studies
revealed that macrocycle B4P4 can inhibit the passive diffusion
of TRH through membranes and reduce its inherent cytotoxicity.
Only small quantities of B4P4 are needed to induce these
effects (e.g., a 1:50 molar ratio of B4P4 compared to TRH). This
behavior stands in contrast to what is seen for most other
macrocyclic inhibitors and points the way to what might be a
new approach to modulating the activity and inherent toxicity of
biologically active small molecules.
[8]
(a) R. D. Myers, G. Metcalf, J. C. Rice, Brain Research. 1977, 126, 105.
(b) J. Hender, T. J. Mccown, R. A. Mueller, T. Hedner, J. Jonason, G. R.
Breese, Acta Physiol Scand. 1987, 130, 69. (c) L. P. Renaud, J. B.
Martin, P. Brazeau, Nature, 1975, 255. (d) G. D. Borowski, C. D.
Garofano, L. I. Rose, R. A. Levy, JCE&MM. 1984, 58, 1977. (e) Y.
Taché, W. Vale, M. Brown, Nature, 1980, 287,149.
[9]
(a) W. Si, P. Xin, Z.-T. Li, J.-L. Hou, Acc. Chem. Res. 2015, 48, 1612.
(b) X. Wu, N. Busschaert, N. J. Wells, Y.-B. Jiang, P. A. Gale, J. Am.
Chem. Soc. 2015, 137, 1476. (c) L. Chen, W. Si, L. Zhang, G. Tang, Z.-
T. Li, J.-L. Hou, J. Am. Chem. Soc. 2013, 135, 2152.
[10] M. Wang, T. Xu J Cell Biochem. 2019, 120, 11921.
[11] Note: Restrains were applied to get a better TRH model in B4P4•TRH•
dioxane • H2O. The SQUEEZE (PLATON) routine was used to the
structure in order to move diffuse electron density associated with
highly disordered lattice water and dioxane molecules in [B4P4•TRH•
dioxane•H2O]. Unfortunately the crystals contain serious disordered
flexible TRH and solvent which prevented sufficient refinement of the
structure (R(F) = 0.21).
Acknowledgements
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Entry for the Table of Contents
The highly selective interaction between artificial polypyridinyl macrocycle and protirelin (TRH) induced unprecedented efficient TRH
inhibition using slight amount (0.003 molar equiv.) of the macrocyclic receptor
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