Polymeric Selectin Ligands Mimicking Complex Carbohydrates: From Selectin Binders to Modifiers of Macrophage Migration

Article abstract of DOI:10.1002/anie.201610395

Novel polymeric cell adhesion inhibitors were developed in which the selectin tetrasaccharide sialyl-Lewis^X(SLe^X) is multivalently presented on a biocompatible poly(2-hydroxypropyl)methacrylamide (PHPMA) backbone either alone (P1) or in combination with O-sulfated tyramine side chains (P2). For comparison, corresponding polymeric glycomimetics were prepared in which the crucial “single carbohydrate” substructures fucose, galactose, and sialic acid side chains were randomly linked to the PHPMA backbone (P3 or P4 (O-sulfated tyramine)). All polymers have an identical degree of polymerization, as they are derived from the same precursor polymer. Binding assays to selectins, to activated endothelial cells, and to macrophages show that polyHPMA with SLe^Xis an excellent binder to E-, L-, and P-selectins. However, mimetic P4 can also achieve close to comparable binding affinities in in vitro measurements and surprisingly, it also significantly inhibits the migration of macrophages; this provides new perspectives for the therapy of severe inflammatory diseases.

Full text of DOI:10.1002/anie.201610395

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Communications
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International Edition: DOI: 10.1002/anie.201610395
German Edition: DOI: 10.1002/ange.201610395
Polymer Glycomimetics
Polymeric Selectin Ligands Mimicking Complex Carbohydrates: From
Selectin Binders to Modifiers of Macrophage Migration
Kai E. Moog, Matthias Barz, Matthias Bartneck, Figen Beceren-Braun, Nicole Mohr,
Zhuojun Wu, Lydia Braun, Jens Dernedde, Elisa A. Liehn, Frank Tacke, Twan Lammers,
Horst Kunz, and Rudolf Zentel*
Abstract: Novel polymeric cell adhesion inhibitors were
developed in which the selectin tetrasaccharide sialyl-LewisX
(SLeX) is multivalently presented on a biocompatible poly(2-
hydroxypropyl)methacrylamide (PHPMA) backbone either
alone (P1) or in combination with O-sulfated tyramine side
chains (P2). For comparison, corresponding polymeric glyco-
mimetics were prepared in which the crucial “single carbohy-
drate” substructures fucose, galactose, and sialic acid side
chains were randomly linked to the PHPMA backbone (P3 or
P4 (O-sulfated tyramine)). All polymers have an identical
degree of polymerization, as they are derived from the same
precursor polymer. Binding assays to selectins, to activated
endothelial cells, and to macrophages show that polyHPMA
with SLeX is an excellent binder to E-, L-, and P-selectins.
However, mimetic P4 can also achieve close to comparable
binding affinities in in vitro measurements and surprisingly, it
also significantly inhibits the migration of macrophages; this
provides new perspectives for the therapy of severe inflamma-
tory diseases.
The selectin family consists of three receptors composed
of calcium-dependent type I transmembrane glycoproteins
with an extracellular lectin domain, which naturally bind to
fucosylated and sialylated glycoprotein ligands. P-selectin is
present on activated platelets and endothelial cells. E-selectin
is exposed on the endothelium after activation by cytokines,
while L-selectin is expressed by leukocytes.[3] Therefore,
selectins are interesting targets for the therapy of inflamma-
tion-related diseases, for example, multiple sclerosis, rheu-
matoid arthritis, and cancer.[4]
While targeting P- and E-selectin can monitor endothelial
cells in the early phases of inflammation,[5] binding to L-
selectin offers the opportunity to visualize local concentra-
tions of leukocytes or even modulate their function.[6] Natural
ligands of selectins within the inflammatory cascade are
glycoproteins: P-selectin glycoprotein ligand-1 (PSGL-1, P-
selectin dissociation constant: 0.3 mm) and E-selectin ligand-
1 (ESL-1, E-selectin dissociation constant: 62 mm). In such
glycoproteins, the sialyl LewisX tetrasaccharide (SLeX) is the
common structure required for binding.[1,2] However, the
binding affinity is modulated by the peptide part of the
respective glycoprotein. In particular, the N-terminal binding
site of PSGL-1 is characterized by O-sulfation of tyrosine
residues. The carbohydrate moiety SLeX itself has different,
but rather low affinities to all selectin members (IC50 = 0.6–
1 mm).[7]
T
he required level of specificity in biological recognition is
often achieved by means of the structural diversity of
glycoproteins, which play important roles in cell–cell inter-
actions.[1] They bind for example, to cell adhesion molecules
(CAMs), like selectins, and are key players in chronic and
acute inflammatory processes.[2]
Natural ligands for selectins, for example, SLeX, have
failed to become anti-inflammatory drugs because they are
often subject to rapid digestion by glycosidases and pepti-
dases in the blood stream. Synthetic selectin inhibitors
representing the binding sites of PSGL-1[8] or E-selectin
ligands (ESL-1)[9] exhibit high and selective affinity to the
corresponding selectins. The binding of synthetic ligands,
however, is often irreversible and causes off-target effects,
which limits their potential medical application.
Thus, the original structures are still of interest, since they
naturally avoid the adverse effects resulting from long-term
or even irreversible blocking of selectins.[10] The therapeutic
use of SLeX derivatives is, however, compromised by their
very complex total synthesis.[11] Therefore besides reducing
synthetic complexity, it is appealing to evaluate whether the
binding affinity and the biological activity of glycoconjugate
selectin ligands can be mimicked by synthetic polymers
presenting the crucial ligand substructures (known from X-
ray crystallography[10c] ) in a polyvalent manner. As only three
of the substructures (galactose, fucose, and sialic acid) are
involved in selectin binding,[10c] synthetic complexity can be
reduced even further.
[*] Dr. K. E. Moog, Dr. M. Barz, Dr. N. Mohr, L. Braun, Prof. Dr. H. Kunz,
Prof. Dr. R. Zentel
Institut fꢀr Organische Chemie
Johannes Gutenberg-Universitꢁt Mainz
Duesbergweg 10–14, 55128 Mainz (Germany)
E-mail: Zentel@uni-mainz.de
Dr. F. Beceren-Braun, Dr. J. Dernedde
Institut fꢀr Laboratoriumsmedizin, Klinische Chemie
und Pathobiochemie
Charitꢂ—Universitꢁtsmedizin Berlin (Germany)
Dr. M. Bartneck, Prof. Dr. F. Tacke
Medizinische Klinik III, Uniklinikum Aachen (Germany)
Prof. Dr. T. Lammers
Institut fꢀr Experimentelle Molekulare Bildgebung (ExMI)
Uniklinikum Aachen (Germany)
Dr. Z. Wu, Dr. E. A. Liehn
Institut fꢀr Molekulare Herz-Kreislaufforschung (IMCAR)
Uniklinikum Aachen (Germany)
Supporting information (experimental details) and the ORCID
identification number for one author of this article can be found
under http://dx.doi.org/10.1002/anie.201610395.
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Recently, glycopolymers are at the focus of great inter-
est.[12] For this comparison of SLeX and its (substructure)
mimetics, we choose the stealth-like, clinically evaluated
poly(2-hydroxylpropyl methacrylamide) (PHPMA)[13] as the
polymer backbone. In order to mimic the multivalency of
natural glycoprotein ligands,[14] the synthetic conjugates were
designed to contain on average 10 SLeX groups or ten times
the three individual monosaccharides randomized along the
polymer chain (Scheme 2). Additionally, 10 tyramine-O-
sulfate groups per polymer were incorporated, which mimic
the O-sulfation of tyrosines in the natural ligands.[5,6]
using palladium hydroxide/charcoal (Pearlmann catalyst) in
a mixture of dioxane/water/acetic acid (10:4:1) yielding the
glycoside 3. This strategy gave exclusively the b-anomer.
As the SLeX derivative 3 (Scheme 1, SI) required a multi-
step synthesis (42 steps) prior to conjugation, the synthesis of
polymer–carbohydrate conjugates separately exposing fuco-
pyranose, galactose, and neuramic acid, each with only a four-
or five-step synthesis, appeared promising. To this end, 11-
amino-3,6,9-trioxaundecyl-a,b-l-fucopyranoside (5), 11-
amino-3,6,9-trioxaundecyl-b-d-galactopyranoside (6) and 11-
amino-3,6,9-trioxaundecyl(4,7,8,9-tetra-O-acetyl)-N-acetyl-
neuraminic acid methyl ester hydrotrifluoracetate (7; see SI)
were synthesized. All compounds contained a hydrophilic 11-
amino-3,6,9-trioxaundecanyl spacer (see SI) for spatial sep-
aration from the polymer after conjugation. Compound 7 was
used in protected form to avoid side reactions during
postpolymerization modifications. In addition, tyramine-O-
sulfate 8 was synthesized by sulfation of tyramine (see SI).
The HPMA polymer was synthesized by the active ester
approach employing the reversible addition–fragmentation
chain-transfer (RAFT) polymerization of pentafluorophenyl
methacrylate according to Barz et al.[13d,16] The RAFT poly-
merization proceeds in a well-controlled manner, yielding
reactive ester polymers (PPFPMA) with a dispersity index
(ꢀI) of 1.2. In agreement with recent results,[17] hydrolysis of
activated esters was avoided. Active ester groups remaining
after the coupling of the carbohydrates were aminolyzed with
2-hydroxylpropylamine, yielding the functionalized PHPMA
polymer. The polymer–carbohydrate conjugates were synthe-
sized by stepwise aminolysis of the polypentafluorophenyl
methacrylates (PPFPMA) with the amine-functionalized
carbohydrates. This ensures the same number of repeating
units along the polymer chain (identical degree of polymer-
ization Pn independent of the molecular weight which
depends on functionalization) for all polymers, as they are
all derived from the same parent PPFPMA. Quantitative
ligation of the functionalized carbohydrates 3, 5, 6,and 7 and
tyramine-O-sulfate 8 was ensured by letting the mixture react
for 15–36 h and monitoring the extent of the reaction by thin-
layer chromatography (see SI). The next conversion (e.g.
aminolysis with 2-hydroxypropylamine to prepare PHPMA)
was started only when no free carbohydrate could be
detected. Acetyl groups were removed using Zemplꢁn
deacetylation, while the sialic acid methyl ester was hydro-
lyzed in aqueous sodium hydroxide at pH 10.5.[18] For model
reactions and a thorough analysis of conjugates see the
Supporting Information. Data of the polymers are listed in
Table 1 and structures are displayed in Scheme 2.
The tetrasaccharide SLeX was synthesized following the
method of Baumann et al.[8b,c] In order to incorporate an
amine function for reaction with the polymer active ester
(Scheme 1), a hydrophilic spacer was introduced by reaction
of the SLeX trichloroacetimidate 1 with Fmoc-protected 11-
amino-3,6,9-trioxa-undecanol (4). The glycosylation was pro-
moted by trimethylsilyl triflate at low temperatures (À50 to
À208C) to achieve high stereoselectivity[15] (see the Support-
ing Information (SI)). This coupling selectively yielded the b-
anomer 2. Tetrasaccharide 2 was partially deprotected in
three steps. The trichloroethoxycarbonyl (Troc) group was
removed with zinc in glacial acetic acid, followed by
acetylation. Then, the benzyl ethers were hydrogenolyzed
Next, the biological activities of SLeX conjugates P1 and
P2 were investigated and compared to those of the tetrasac-
charide SLeX 3 and of the mimetic polymers P3 and P4, which
present the fucopyranose, galactose and neuramic acid
randomly along the polymer backbone.
First, in vitro binding affinities towards the selectins were
determined in competition studies applying a surface plasmon
resonance (SPR) setup (see SI).[19] The IC50 values for SLeX 3,
P1, P2, P3, and P4 (lower IC50, higher binding affinity) are
displayed in Table 2.
Scheme 1. Last three steps in the 42-step synthesis of SLeX derivative 3
for polymer conjugation. Bn=Benzyl, Fmoc=fluorenylmethoxycar-
bonyl, TFAÀ =trifluoracetate (purification by semipreparative HPLC
with ACN/H2O (1:1) and 0.1 % TFA, see SI), TMSOTf=trimethylsilyl-
triflate, Troc=2,2,2-trichlorethoxycarbonyl. For synthetic details see
Ref. [8b,c] and SI.
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Table 1: Characteristics of SLeX 3 and polymer–carbohydrate conjugates
P1–P4 labeled with 1 mol% of the fluorophore Oregon Green 488 (see
Scheme 2).
Table 2: IC50 values of polymer–carbohydrate conjugates towards bind-
ing of E-, L-, and P-selectins.[a]
E-selectin[b] [nm]
L-selectin[b] [nm]
P-selectin[b] [nm]
Carbohydrate[a]
content
[% of repeating
units]
Tyramine sulfate
Pn or Mn
SLeX-S
PHPMA
P1
P2
P3
170000
N.I.
39000
11000
N.I.
N.I.
N.I.
7000
900
85000
10000
N.I.
N.I.
26000
70
200000
6000
content [% of repeating [kgmolÀ1
units]
]
SLeX 3
PPFPMA
PHPMA
P1
P2
P3
100
–
1.95[a]
100 or 25.2[b]
100 or 14.1[c]
100 or 24.1[c]
100 or 25.4[c]
100 or 24.8[c]
P4
298000
–
–
–
[a] N.I.: no inhibition up to 1 mm concentrations; low IC50 values
correspond to strong binding affinities. [b] Determined by competitive
SPR-based binding assay (see SI); IC50 values display the concentration,
which causes reduction of binding of 50% compared to the control.
SLeX10 (3)[d]
SLeX10 (3)[d]
Gal10, Fuc10,
Neu10[d]
10[d]
–
P4
Gal10, Fuc10,
10[d]
100 or 26.1[c]
Neu10[d]
requires a carbohydrate structure.[9] The polymer–carbohy-
drate mimetics P3 and P4 generally display higher IC50 values
(lower binding affinities) compared to those bearing SLeX
derivatives. After sulfation, the IC50 values of P4 showed two
orders of magnitude better binding for P-selectin than for its
non-sulfated counterpart P3 and reached a comparable (L-
selectin) or even lower (P-selectin) level than P1. The
conjugate P2 (10% SLeX and 10% tyramine-O-sulfate) had
the highest binding affinity of all investigated compounds. In
this case, IC50 values of 70 nm for P-selectin, 900 nm for L-
selectin, and 11 mm for E-selectin were achieved. In compar-
ison to E-selectin, the affinities of P1 and P2 are slightly lower
than the natural ligand, with IC50 values of 39 and 11 mm
(compared to IC50 = 62 mm for the monovalent glycoprotein
ESL-1). Altogether, these data show that sulfated carbohy-
drate mimetics like P4 can achieve binding affinities that are
very similar to those of sulfated polymers with SLeX, which
constitute excellent binders to E-, L-, and P-selectins.
Values determined by [a] ESI-MS or [b] GPC. [c] Mn recalculated from the
Pn of PPFPMA for the new molecular structure. [d] The degree of
functionalization was obtained proving full conversion of the reactive
amines 3, 5, 6, 7, and 8 with PPFPMA.
After the determination of binding affinities by an SPR
assay, the question remains whether polymer–SLeX conju-
gates P1 and P2 as well as their glycomimetics P3 and P4 also
bind efficiently to selectins expressed on different cells. To
address this question, first two-photon laser scanning micros-
copy (TPLSM) studies of binding and cellular uptake of the
fluorescent-labeled conjugates P1–P4 in human umbilical
vein endothelial cells (HUVEC) with and without TNF-
a stimulation were conducted in a flow chamber setup. This
experimental setup (flow rate of 0.25 mLminÀ1) mimics the
blood flow in vivo (see Figure 1, upper line). The cytokine
TNF-a induces the expression of P-selectin and E-selectin by
HUVEC.[20] Logically, in the absence of TNF-a, polymer–
carbohydrate conjugates P1–P4 should not bind to HUVECs.
And as shown in Figure 1 (middle line), cell-associated
fluorescence is not detectable without endothelial cell stim-
ulation with TNF-a. Neither the control polymer PHPMA
nor the polymer–carbohydrate conjugates showed cellular
binding or internalization into HUVEC. This excludes
unspecific binding in continous flow at the applied conjugate
concentration of 1 mm.
Scheme 2. Polymer–carbohydrate conjugates P1–P4 with SLeX (P1/P2)
and carbohydrate mimetics (P3/P4) (see Scheme 1). P1 and P3 are not
sulfated (q=0%), while P2 and P4 are (q=10%).
The IC50 values for binding of P1–P4 to L- and P-selectins
were in the nm to mm range and are a factor of 10–100 lower
than those to E-selectin. In line with results reported for
nature-inspired synthetic ligands[8] and polyglycidol-based
ligands,[19] the affinity to L- and P-selectins is enhanced, when
sulfate groups are present in the macromolecule (see Haag
et al.; describing highly sulfated polyglycidols without any
special carbohydrate structure as ligands for L- and P-
selectins (30–90 nm)[19c]). Binding to E-selectin, however,
When endothelial cells were, however, stimulated with
TNF-a, enhanced cell-associated fluorescence and accumu-
lation of polymer–carbohydrate conjugates inside HUVEC
became visible (Figure 1, lower line) for the sulfated polymers
P2 and P4. In contrast, neither non-sulfated polymers P1 and
P3 displayed cell-associated fluorescence (see SI). Appa-
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Figure 2. Binding of polymeric selectin ligand mimetics to macro-
phages and effects on macrophage migration. Primary human macro-
phages were generated by monocyte culture in RPMI1640 supple-
mented with 5% serum for seven days. A) Flow cytometry based
quantification of conjugate-associated fluorescence after 60 min of
incubation at a concentration of 3 mm. Histogram overlays reflect the
fluorescent signal of selectin-directed constructs and their binding to
macrophages. B) Scheme of transwell assay before (top) and after
(bottom) macrophage migration. C) Quantification of macrophage
migration after 16 h. Prior to the experiment, cells were preincubated
for 1 h with the conjugates. Mean data of n=5. *P<0.05 (StDev).
Figure 1. Schematic depiction and two-photon microscopy analyses of
the binding of polymer–carbohydrate conjugates P2, P4, and PHPMA
to human umbilical vein endothelial cells (HUVEC) depending on
TNF-a stimulation. The images show DAPI staining of the nucleus
(blue), WGA-AF562 staining of the cell membrane (red), and OG488-
labeled polymers (green) after 1 h of incubation. Yellow color indicates
colocalization of the polymers with the cell membrane.
caused by P2 is an order of magnitude higher than that of the
mimetic carbohydrate–polymer P4.
rently, sulfate-dependent electrostatic interactions of the
ligands with P-selectin enhance cell adhesion and uptake.
Since we observed no pronounced difference between the
sulfated SLeX-HPMA polymer P2 and the sulfated Sia-Fuc-
Gal-HPMA copolymer P4, it seems that even the mimetic
polymer P4 bears significant potential to bind to endothelial
cells already in the early stages of inflammation when P-
selectin is expressed.
Having demonstrated efficient binding to P- and E-
selectins on stimulated endothelial cells, we studied L-selectin
binding in more detail. L-selectin is expressed on leukocytes,
for example, macrophages. Binding to L-selectin is of
particular interest since the local accumulation of macro-
phages is a hallmark of chronic inflammation and cancer.[21]
Depending on their specific properties, nanoparticle-based L-
selectin inhibitors may, however, also alter the activation state
of macrophages and their functions in inflammation.[22] As
macrophages are sensitive to anionic charges in polymers, like
sulfation in P2 and P4, we also prepared a sulfated carbohy-
drate-free reference polymer (S-PHPMA, see SI), in which
10% of the repeating units are functionalized with tyramine-
O-sulfate.
More importantly, the binding of the corresponding
ligands to selectins may also affect macrophage functions,
for instance, their migratory properties. Therefore, we pre-
incubated macrophages for 60 min with the different poly-
mer–carbohydrate conjugates at a concentration of 3 mm to
allow for binding. Then, the migration of macrophages was
assessed for 16 h in a standardized chemotaxis assay (Fig-
ure 2B).[23] Interestingly, P4 now led to a significant inhibition
of macrophage migration (Figure 2C), while the SLeX-
containing conjugates P1 and P2 reduced macrophage
migration only moderately (Figure 2C). PHPMA and S-
PHPMA had hardly any effect. The relatively high standard
deviations observed for some of the groups treated with
mimetics can be explained by intradonor differences in the
expression of surface molecules on primary human cells,[24] as
well as by variability in the induced biological response
(which is absent in the case of controls). In spite of this
variability, it is clear that polymer P4—mimicking the SLeX
binding motif—modifies macrophage migration substantially,
while P2 with the natural SLeX ligand binds more efficiently,
but has only a minor effect on macrophage migration.
Although the exact reasons for these findings need to be
investigated in more detail in future experiments, they
provide a first indication that even simple glycopolymers
mimicking complex carbohydrates may be used to modulate
macrophage migration and/or activation.
At first, the binding of conjugates to primary human
macrophages after 60 min of incubation at a concentration of
3 mm was investigated by flow cytometry. As displayed in
Figure 2A, conjugate P2 displayed the highest cell-associated
fluorescence, followed by P4, P1, and P3. This result is in line
with the binding affinity to L-selectins obtained from the SPR
assay (Table 2). In this case, the cell-associated fluorescence
In this context, the unexpected efficiency of the rather
simple sulfonated glycomimetic polymer P4 is particularly
4
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pharmacologically useful properties, and further exploration
is needed to reveal the full potential of multivalent polymer–
carbohydrate conjugates.
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Acknowledgements
Support by the German Research Foundation (SFB 1066) and
the European Research Council (ERC-StG-309495) is grate-
fully acknowledged. We thank Martin Scherer for resynthe-
sizing S-PHPMA and Regina Holm for help with preparing
the manuscript.
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Conflict of interest
The authors declare no conflict of interest.
ˇ
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Keywords: glycopolymers · nanomedicine · PHPMA ·
polymer–carbohydrate conjugates · sialyl-Lewisx mimetics
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Angewandte
Communications
Chemie
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Manuscript received: October 24, 2016
Final Article published: && &&, &&&&
6
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These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Polymer Glycomimetics
Complex carbohydrates like sialyl-LewisX
(SLeX) play a role in cell–cell recognition
and inflammatory processes. A biocom-
patible polymer that presents SLeX mul-
tivalently was compared with corre-
K. E. Moog, M. Barz, M. Bartneck,
F. Beceren-Braun, N. Mohr, Z. Wu,
L. Braun, J. Dernedde, E. A. Liehn,
F. Tacke, T. Lammers, H. Kunz,
sponding polymeric glycomimetics. For
one of the mimetics the selectin binding
affinity is similar to that of the SLeX–
polymer system. It inhibits macrophage
migration and offers new perspectives for
therapy of severe inflammatory diseases.
R. Zentel*
&&&& — &&&&
Polymeric Selectin Ligands Mimicking
Complex Carbohydrates: From Selectin
Binders to Modifiers of Macrophage
Migration
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!