Pentavalent pillar[5]arene-based glycoclusters and their multivalent binding to pathogenic bacterial lectins

Article abstract of DOI:10.1039/c6ob00220j

Anti-adhesive glycoclusters offer potential as therapeutic alternatives to classical antibiotics in treating infections. Pillar[5]arenes functionalised with either five galactose or five fucose residues were readily prepared using CuAAC reactions and eval

Full text of DOI:10.1039/c6ob00220j

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ARTICLE TYPE
Pentavalent pillar[5]arene-based glycoclusters and their multivalent
binding to pathogenic bacterial lectins
a,b
b
b
c
a
Nicolas Galanos, Emilie Gillon, Anne Imberty,* Susan E. Matthews, and Sébastien Vidal*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Antiꢀadhesive glycoclusters offer potential as therapeutic alternatives to classical antibiotics in treating
infections. Pillar[5]arenes functionalised with either five galactose or five fucose residues were readily
prepared using CuAAC reactions and evaluated for their binding to three therapeutically relevant bacterial
lectins: LecA and Lec B from Pseudomonas aeuruginosa and BambL from Burkholderia ambifaria.
Steric interactions were demonstrated to be a key factor in achieving good binding to LecA with more
flexible galactose glycoclusters showing enhanced activity. In contrast binding to the fucoseꢀselective
lectins confirmed the importance of topology of the glycoclusters for activity with the pillar[5]arene
ligand proving a selective ligand for BambL.
1
0
3
4
Introduction
infectivity have been identified; the galactose specific LecA and
LecB,
35, 36
which binds to fucose and fucoseꢀcontaining
oligosaccharides, particularly Lewis a trisaccharide. Whilst LecA
has been implicated in damage to the alveolae and uptake of the
LecB has been demonstrated to be
involved in cell adhesion making both lectins ideal targets for
therapeutic intervention.
In contrast to the tetrameric LecB, the fucose selective lectin
BambL from Burkholderia ambifaria self assembles into a
trimeric βꢀpropeller fold presenting six binding sites. B.
ambifaria, a gram negative organism, is a component of the
Burkholderia cepacia complex (BCC) which is responsible for
both acute and chronic respiratory disease and, in some cases,
cepacia syndrome particularly in patients with cystic fibrosis.
Although, the role of BambL in infection has not been fully
characterised, it has been shown to bind to blood group
1ꢀ5
1
2
2
3
3
4
4
5
0
5
0
5
0
5
Pillararenes, the newest members of the calixarene family,
5
5
6
6
7
7
8
0
5
0
5
0
5
0
6
have, since their introduction in 2008, been rapidly developed
for a wide range of applications including sensors, rotaxane
wheels and supramolecular polymers.
37, 38
bacteria into cells,
1
ꢀ5
In contrast to
15
calix[4]arene and resorcin[4]arene, pillar[5]arene offers a highly
rigid and symmetrical structure with two identical faces for
functionalisation, and thus higher valency on a small platform,
and is inherently chiral. Synthetic procedures have been
developed for the preparation of both fully and partially
functionalised pillar[5]arenes. In particular, use of nonꢀ
symmetrically functionalised alkoxybenzene derivatives in the
condensation reaction provides platforms featuring five regularly
39
40
7
distributed points of functionalisation whereas further selective
8, 9
functionalisation can be achieved using statistical mixtures in
the condensation and through post cyclisation approaches.
The biological property of multivalency has attracted
significant attention for the development of cluster molecules
capable of highꢀaffinity binding, based on a wide range of
topologically different scaffolds.
interest that has recently come to the fore is the development of
antiꢀadhesive molecules against pathogen infections.
Glycoclusters capable of disrupting bacterialꢀtoꢀhuman cell
interactions and formation of bacteria biofilms through
interaction with bacterial lectins have been designed.
have previously developed a topologically diverse series of such
glycoclusters based on calix[4]ꢀ
39
41
associated oligosacacharides and structurally similar lectins
have been implicated in inflammation in epithelial cells making it
an interesting target for multivalent glycoclusters. Additionally,
comparison of binding to tetrameric LecB versus hexameric
BambL provides fundamental insights into the role of topology of
glycoclusters in achieving selective lectin binding.
The potential of pillar[5]arene scaffolds for the development of
antimicrobial glycoclusters was first shown using a decaꢀ
mannose functionalised pillar[5]arene which was able to inhibit
adhesion of Escherichia coli to red blood cells through
interaction with the FimH adhesin. Similarly, pillar[5]areneꢀ
based glycoclusters, featuring five galactose moieties, facilitated
agglutination of E. coli, although the specific lectin interactions
were not identified. The potential to use pillar[5]arene based
1
0ꢀ12
One particular area of
13ꢀ22
We
42
2
3, 24
25
and calix[6]arenes,
26
27, 28
25, 29ꢀ32
resorcin[4]arenes, fullerenes,
calix[4]areneꢀbased glycoclusters have been demonstrated to alter
and porphyrins.
The
43
the lectinꢀmediated infectivity of Pseudomonas aeruginosa in
rotaxanes to simultaneously provide inhibition of both LecA and
LecB has also been described. [2]Rotaxanes featuring bisꢀ
fucosylated stoppers combined with decaꢀgalactosylated wheels
provided the ideal arrangement for good binding with LecB,
23
lungs.
P. aeruginosa is an opportunistic pathogen, with emerging
drug resistance, responsible for severe lung infections in immuneꢀ
compromised patients. Two major soluble lectins involved in
44
3
3
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through an aggregative interaction and LecA, through clustering.
More recently, we have reported the development of
decavalent pillar[5]arenes, featuring either galactose or fucose
epitopes, and evaluated binding against LecA, LecB and
45 triethyleneglycol galactoside afforded the desired acetylated
glycocluster 8. Unmasking of the protecting groups provided the
desired galactose glycocluster 9.
45
5
BambL. In this series, increased valency resulted in higher
affinity as did increasing flexibility of the sugar linkers. The
present study describes the synthesis and characterisation of
pentavalent pillar[5]arenes functionalised with either galactose or
fucose and investigates their binding to LecA, LecB and BambL.
The use of a combination of biophysical techniques, including
hemagglutination inhibition assay (HIA), enzymeꢀlinked lectin
assay (ELLA), isothermal titration microcalorimetry (ITC) and
surface plasmon resonance (SPR) to determine the binding
interactions is also reported.
1
0
15
Results and Discussion
Synthesis of glycoclusters
Scheme 2. Synthesis of a galactosylated pentavalent pillar[5]areneꢀbased
50 glycocluster using a pentaꢀpropargylated core scaffold. Reagents and
2
4ꢀ28, 46, 47
Building on our previous experience
in the development
conditions: (a) paraformaldehyde, BF
azidoꢀ3,6ꢀdioxaꢀoctyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀβꢀ
3
•OEt
2
, Cl(CH
2
)
D
2
Cl, r.t., 50%; (b) 1ꢀ
ꢀgalactopyranoside,
of glycoclusters using Cu(I)ꢀassisted azideꢀalkyne cycloaddition
48
(
CuAAC), the synthetic route focused on the preparation of
4
CuSO , sodium ascorbate, DMF, 110°C, 15 min, µwaves, 76%; (c)
20
25
30
pillar[5]arenes bearing either five azido or five alkynyl
substituents for subsequent reaction with the corresponding
alkynyl or azido carbohydrate derivatives.
In both cases functionalisation was introduced prior to
cyclisation by using nonꢀsymmetrical alkoxybenzenes. The
pentaꢀazido pillar[5]arene 3 was accessed through the preparation
MeOH, Et
3 2
N, H O, r.t., 16 h, >95%.
5
6
6
7
7
8
5
0
5
0
5
0
It is important to note that the chirality induced by the
pillar[5]arene ring system
diastereoisomers upon conjugation with carbohydrates. It has
previously been reported that separation of nonꢀsymmetrical
pillar[5]arenes can be achieved, but only when there are
substantial differences between the two substituents. Separation
50
results in the formation of
4
2
51
of the pentaꢀbromo derivative 2. BF •OEt2 mediated
3
macrocyclization of the bromoꢀprecursor
1
with paraꢀ
52
of 7 has not proved possible although the diastereoisomers of a
specific click conjugate have been isolated. Not surprisingly, the
separation of the individual diastereoisomers of 5 and 9, bearing a
methyl group, was not successful even after careful column
chromatography. Although these isomeric mixtures could affect
the interpretation of the binding studies towards lectins, the
spatial arrangements of the carbohydrate epitopes for pentavalent
scaffolds will not alter greatly the general presentation of the
binding partners to the lectins.
In addition to the two enantiomers generated during the
macrocyclization process, several conformers can also arise from
the rotation of each arene ring (Figure 1). The formation of the
pillar[5]arene macrocycle provides a mixture of 4 possible
constitutional isomers A1-4 (Figure 1, top). These four isomers
can rotate each of their arene moieties to provide a series of eight
formaldehyde gave pillar[5]arene 2 (Scheme 1). Subsequent
azidation readily provided 3 suitable for CuAAC conjugation
4
5
with the previously reported propargyl galactoside and fucoside
affording the desired acetylated glycoclusters 4a-b. Solvolysis of
the acetates provided the water soluble glycoclusters 5a-b for
binding assays.
7
rotational isomers (e.g. A1 to F , Figure 1, bottom). The
conformer A can have one aromatic ring rotated by 180° to
generate the conformer B . Further rotations of aromatic moieties
toward the right hand side provide a series of rotational
1
1
1
conformers C , D , E and finally F . When considering
1
1
1
1
conformers A and F , they are mirror images of each other and
1
1
3
5
0
Scheme 1. Synthesis of pentavalent pillar[5]areneꢀbased glycoclusters
therefore enantiomers, similarly for B and E and also C and
1
1
1
using
paraformaldehyde, BF
00°C, 12 h, 91%; (c) propargyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀβꢀ
galactopyranoside or propargyl 2,3,4ꢀtriꢀOꢀacetylꢀαꢀ
CuI, iPr NEt, DMF, 110°C, 15 min, µwaves, 87% (4a), 93% (4b); (d)
MeOH, Et N, H O, r.t., 16 h, >95% (5a and 5b).
a
pentaꢀazido core scaffold. Reagents and conditions: (a)
D . These rotations are possible due to the small size of the
1
3
•OEt , Cl(CH Cl, r.t., 84%; (b) NaN , DMF,
2
2
)
2
3
methoxy substituents in an inꢀcavity rotation. Several other
1
Dꢀ
D
ꢀfucopyranoside, 85 conformations can also be adopted but are not depicted. These
4
2
occur from rotation at nonꢀcontiguous aromatic moieties and the
conformers presented in Figure 1 illustrate the most simple and
stepꢀbyꢀstep process. Hence, variable temperature NMR
experiments can provide an insight on such isomeric mixtures.
3
2
More conveniently, the pentaꢀalkynyl pillar[5]arene scaffold 7
was obtained directly from its precursor 6 and paraformaldehyde
49
90
(Scheme 2).
Conjugation with the azidoꢀfunctionalized
2
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the single technique for evaluation of the dependence of binding
of glycocluster 5b to LecB and BambL, giving access to the
stoichiometry of the binding partners for each multimeric
25 complex formed. In addition, two decavalent pillar[5]areneꢀbased
glycoclusters PillarGal10 and PillarFuc10 were also included in
the study for comparison (Figure 3).
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
A1
A3
A2
A4
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
R
R
N
N
N
R
N
R
N
N
N N
O
N
N
N
N
N
N
R
N
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
O
O
O
A1
B1
C1
O
O
N
O
O
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
N
N
R
N
N
N N
N
D1
N
N
N
N
R
R
N
R
N
N
R
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
OH OH
PillarGal
O
E1
F1
O
10
R =HO
O
OMe groups
Other chains
O
OH
and several other conformers...
O
O
O
Me
O
Figure 1. Schematic diagram of the potential isomers that can be
formed during the macrocyclization.
R =
OH PillarFuc10
OH
HO
Figure 3. Structures of the galactosylated (PillarGal ) and
fucosylated (PillarFuc ) decavalent pillar[5]areneꢀbased
10
glycoclusters.
1
0
5
This conformational isomerism could be easily observed in both
H and C NMR (Figures 2, S1 and S2). Several peaks appeared
30
1
13
as collections of singlets showing the conformer population in
solution indicating that interconversion was slower than the NMR
timescale. A slight dependence on temperature was observed
LecA Binding studies
Two galactosylated glycoclusters (5a and 9) were evaluated
1
0
since heating from 20 to 100°C accelerated the equilibrium and 35 for their ability to bind to LecA (Table 1) and compared with the
1
13
the NMR spectra displayed sharper peaks both in the H and
C
previously described PillarGal . The initial HIA study
10
NMR data (Figures 2, S1 and S2).
highlighted efficient binding of these multivalent ligands to LecA
which was confirmed in ELLA studies. Both new ligands showed
moderate improvement (5a β = 23, 9 β = 73) in binding based on
their multivalency. The significantly enhanced activity of 9 could
be ascribed to the longer triethyleneglycol linker arms in this
conjugate providing greater flexibility for binding of the
galactose moieties to the lectin.
ITC was used to gain an insight into the thermodynamic
parameters governing the binding to LecA and also the
stoichiometry of binding. The same enhancement in binding was
observed for the more flexible glycocluster 9 over 5a although
4
4
5
5
6
0
5
0
5
0
both ligands gave K values in the subꢀmicromolar range.
d
The stoichiometry (N) for the complex generated between the
lectin and the glycocluster also varied depending on the linker.
Thus compound 5a interacted with two or three LecA monomers
(N = 0.40), while, in contrast, 9 bound to five LecA monomers (N
1
= 0.17) indicating that all the carbohydrate epitopes are engaged.
This variation is probably a consequence of the longer
triethyleneglycol linker arm allowing reduced steric hindrance in
the binding of multiple LecA monomers.
SPR experiments using LecA attached on the chip were also
undertaken and affinity was evaluated using a thermodynamic
approach. Typical curves were observed as the glycoclusters 5a
and 9 were circulated. The SPR and ITC affinities were in the
same range demonstrating that the immobilization of LecA on the
Figure 2. Partial H NMR data (400 MHz, DMSOꢀd ) measured
6
1
5
for the brominated pillar[5]arene 2.
Binding studies
The binding properties of glycoclusters 5a and 9 with LecA were
evaluated
using
four
complementary
techniques;
hemagglutination inhibition assay (HIA), enzymeꢀlinked lectin
assay (ELLA), isothermal titration microcalorimetry (ITC) and
surface plasmon resonance (SPR). In contrast ITC was chosen as
2
0
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45
chip surface did not modify the binding to multivalent ligands. As
analogous decaꢀfunctionalized pillar[5]arene (PillarGal ) this
10
with the other techniques, enhancement of binding was again 10 is not the case in both HIA and ELLA studies and only a
seen for the more flexible 9 over 5a in SPR studies reinforcing
the importance of flexibility to LecA binding.
moderate improvement is seen in ITC. . The stoichiometry
observed in ITC may provide a rationale for this as despite ten
groups being available for binding, only five LecA tetramers
interact with the glycoclusters and thus no advantage of the
5
It is interesting to compare the results seen here with those of
4
5
our previously reported decavalent pillar[5]arenes. Whilst it
might be expected that increasing the valency would enhance 15 further five available carbohydrate epitopes is seen.
binding further, in the case of glycocluster 9 in comparison to its
Table 1. HIA, ELLA ITC and SPR measurements for binding of pillar[5]areneꢀbased glycoclusters to LecA
HIA
ELLA
ITC
–T∆S
(kJ.mol )
SPR
th
(nM)
a
Compound
MIC
ꢀM)
IC50
(ꢀM)
b
c
–∆H
(kJ.mol )
K
(nM)
d
b
K
d
β
N
ꢁ1
ꢁ1
β
(
d
e,f
βꢁGalOMe
6250
10
2
658
1
0.8
39
15
70 000
1
n.m.
508
337
47
5a
29
9
23
73
3
0.40±0.02
0.17±0.01
0.20±0.01
82±3
174±9
115±2
47.4
138
78
931±30
586±38
366±129
75
9
119
191
g
PillarGal10
5
218
a
b
Minimum inhibitory concentration (MIC) required to inhibit the agglutination of erythrocytes. Calculated using methyl βꢀd
D
ꢀgalactopyranoside (βꢀ
c
47
GalOMe) as monovalent reference. Stoichiometry of binding defined as the number of glycoclusters per monomer of LecA. Data from previous report.
e
f
g
45
20
n.m. = Not measured. RU shift was too weak due to the low molecular weight of βꢀGalOMe. Data from previous report.
resulted in a loss of affinity at each site. The importance of ligand
orientation is further demonstrated through comparison with
PillaFuc10 which is able to interact with additional binding sites
and shows enhanced binding and a positive multivalent effect.
In contrast, 5b proved to be an excellent ligand for BambL
LecB and BambL Binding studies
3
5
The fucosylated glycocluster 5b was evaluated for its potential
as a LecB and BambL ligand by ITC (Table 2) and showed
considerable selectivity between the two topologically different
fucose binding lectins, with high affinity only towards BambL.
2
5
(
Table 2) surpassing previously reported glycoclusters based on
The millimolar K value for LecB was disappointing compared to
53
d
40 mannose and phosphodiester cores and the higher valency
pillar[5]arene derivatives including PillarFuc . Interestingly
the monosaccharide ligand and to our previously reported
calix[4]arene derivatives with no enhancement achieved through
presentation on a multivalent scaffold. The stoichiometry (N) of
the lectinꢀglycocluster complex indicated three LecB monomers
bound to the pentavalent ligand 5b (N = 0.29) but clearly the
orientation of the carbohydrate epitopes is not favorable and
45
10
the β value of 45 for the pentavalent ligand 5b with a
stoichiometry (N = 0.71) indicated that only a fraction of the five
carbohydrate epitopes were used in the binding and that one or
two lectin monomers are bound.
1
1
30
45
Table 2. ITC measurements for binding of pillar[5]areneꢀbased glycoclusters to LecB and BambL
b
–∆H
kJ.mol )
–T∆S
(kJ.mol )
K
(nM)
d
a
Compound
Lectin
N
ꢁ1
ꢁ1
β
(
c
c
c
αꢁFucOMe
LecB
LecB
LecB
0.77±0.03
41±1
5
430±10
1
5b
0.29±0.01
0.13±0.01
106±19
250±2
73
1402±45
280±33
0.3
1.5
d
PillarFuc10
213
e
αꢁFucOMe
BambL
BambL
BambL
2.02
48±2
14
35
960±30
21±7
1
5b
0.71±0.01
0.35±0.02
79±3
201±5
b
45
17
d
PillarFuc10
160
57±16
a
Calculated using monovalent methyl αꢀ
monomer of LecB. Data from previous report. Data from previous report. Data from previous report.
L
ꢀfucopyranoside (αꢀFucOMe) as reference. Stoichiometry of binding defined as the number of glycoclusters per
c
54 d
45 e
39
platform for interaction with bacterial lectins. Pillar[5]arenes
were prepared bearing either five alkynyl or azido functional
groups and glycoclusters featuring either galactose or fucose
moieties were readily produced using CuAAC. Binding of
galactose functionalised pillar[5]arenes to LecA from P.
aeruginosa was shown to be heavily dependent on linker length
between the core and carbohydrate and that this also plays a role
5
0
Conclusions
The potential of multivalent antiꢀadhesive drugs as therapeutics
for drugꢀresistant bacterial infections in immuneꢀcompromised
patients is an area of considerable interest. Here we have shown
that the pillar[5]arene scaffold, when nonꢀsymmetrically
functionalised to present five glycosides, acts as an excellent
60
55
4
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6
6
7
7
8
8
9
9
0
5
0
5
0
5
0
5
8. Z. Zhang, B. Xia, C. Han, Y. Yu and F. Huang, Org. Lett., 2010, 12,
285ꢀ3287.
in stoichiometry, with the best ligand demonstrating the ability to
interact simultaneously with five separate LecA tetramers.
Considerable variation in binding of the fucosylated glycoclusters
to the two fucose specific lectins LecB from P. aeruginosa and
BambL from B. ambifaria was observed. This glycocluster
proved to be an excellent ligand for BambL with low nanomolar
affinity whereas no improvement in binding compared to a
monovalent ligand was observed for LecB. This result
demonstrates the importance of lectin topology in analysing
binding selectivity.
An interesting aspect of these glycoclusters is their
stereochemistry as each was obtained as a 1:1 diastereoisomer
mixture due to the cyclisation of nonꢀsymmetric arenes. Some
selectivity in binding may be observed between the
diastereoisomers and thus the data presented here can be
considered to be an average result. Our further studies will focus
on the preparation of pillar[5]arene derivatives which can be
chromatographically separated in order to determine whether the
chirality of the glycocluster affects binding strength and
selectivity.
3
9
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1
2
0
5
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Chimie) for additional funding and the Royal Society for funding
work undertaken in S.E.M.’s laboratory (JP090449). Prof J.ꢀF.
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