Multivalent thioglycopeptoids via photoclick chemistry: Potent affinities towards LecA and BC2L-A lectins

Article abstract of DOI:10.1039/c5cc04646g

Solution-phase synthesis of linear and cyclic β- and α,β-peptoids was coupled to photo-induced thiol-ene coupling reaction to readily access multivalent thioglycoclusters. A tetrameric cyclic β-peptoid scaffold displaying 1-thio-β-D-galactose or 1-thio-α-D-mannose has revealed by ITC experiments efficient binding potency for bacterial lectins LecA and BC2L-A, respectively.

Full text of DOI:10.1039/c5cc04646g

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Multivalent thioglycopeptoids via photoclick
chemistry: potent affinities towards LecA and
Cite this:DOI: 10.1039/c5cc04646g
BC2L-A lectins†
C. Caumes,ab E. Gillon,c B. Legeret,ab C. Taillefumier,ab A. Imberty*c and S. Faure*ab
Received 5th June 2015,
Accepted 23rd June 2015
DOI: 10.1039/c5cc04646g
www.rsc.org/chemcomm
Solution-phase synthesis of linear and cyclic b- and a,b-peptoids of ligation has been widely exploited in the field of polymer
was coupled to photo-induced thiol–ene coupling reaction to science7 and this century-old reaction8 has ignited growing interest
readily access multivalent thioglycoclusters. A tetrameric cyclic in the past few years for preparing multivalent carbohydrate-based
b-peptoid scaffold displaying 1-thio-b-D-galactose or 1-thio-a-D- constructs due to its ‘‘click chemistry profile’’.9 Well-defined
mannose has revealed by ITC experiments efficient binding potency thioglycoclusters were first efficiently prepared by the group
for bacterial lectins LecA and BC2L-A, respectively.
of Stoddart from b-cyclodextrin scaffolds using protected
1-thiosugars.10 The method was further extended to other
The design of multivalent glycoconjugates with high-affinity for scaffolds including peptides, calixarenes and dendrimers. How-
proteins that possess multiple glycoside binding sites such as ever the reaction conditions, notably an excess of carbohydrate
lectins and antibodies has been widely developed during the partners, the use of organic solvents, protected carbohydrates
last decades.1 Lectins are carbohydrate-specific proteins that and purifications by chromatography were sometimes quite far
mediate numerous cellular recognition events: development, from click chemistry criteria.11 By adapting continuous flow
differentiation, morphogenesis, fertilisation, immune response, chemistry to photochemical TEC, Hartmann’s group demon-
implantation, cell migration and cancer metastasis.2 Lectins contain strated the power of this reaction to access sequence-defined
two or more specific sugar-combining sites and as a consequence carbohydrate-functionalised oligo(amidoamines).12 The TEC
display strong avidity towards clustered sugars compared to reaction is a particularly appealing ligation method for the
monomeric ones. The lectin-binding efficiency and specificity preparation of heteroglycoclusters when combined with the
of glycoclusters have been found to be dependent not only on the copper(I)-catalysed alkyne–azide cycloaddition (CuAAC)13 or
epitope density but also on the nature of the backbone and on with the thiol–chloroacetyl coupling (TCC).14
the geometrical characteristics of the multivalent assembly.3
a-Peptoids (N-substituted glycine oligomers) and b-peptoids
In the field of multivalent glycoside recognition, although (N-substituted b-alanine oligomers) are peptidomimetics char-
poorly studied, S-glycoclusters present notable benefits over acterised by resistance to proteases, rapid cellular uptake, and
their O-glycoside counterparts, especially in terms of chemical straightforward synthesis with a great potential for diversity.15
stability and low susceptibility to enzymatic degradation.4 Glycopeptoids have been developed as proteolytically stable
Furthermore due to similar spatial arrangement of S- and glycopeptide mimics and the use of peptoid to access multivalent
O-glycosides, many lectins tolerate the O to S replacement, glycocluster constructs has proven particularly interesting.16 The
and some have even stronger affinity toward S-glycosides than CuAAC reaction has been widely used for functionalizing peptoid
the corresponding O-glycosides.5 Thioglycoclusters can be pre- scaffolds and particularly for accessing glycoclusters.17 By con-
pared by photochemical thiol–ene coupling (TEC reaction) between trast, the TEC reaction still remains nearly unexploited in the
1-thiosugars and alkene-functionalized scaffolds (Fig. 1).6 This type peptoid field.18 The only access to peptoid-type thioglycoclusters
a
´
´
Universite Clermont Auvergne, Universite Blaise Pascal, Institut de Chimie de
Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France
b
c
`
CNRS, UMR 6296, ICCF, F-63178 Aubiere Cedex, France.
E-mail: Sophie.Faure@univ-bpclermont.fr
´
CERMAV, UPR5301, CNRS and Universite Grenoble Alpes, BP 53, 38041 Grenoble,
France. E-mail: anne.imberty@cermav.cnrs.fr
† Electronic supplementary information (ESI) available: Experimental details,
compound characterisations, ITC experiments. See DOI: 10.1039/c5cc04646g
Fig. 1 Multivalent photochemical thiol–ene reaction.
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reaction criteria.11 First of all, free 1-thiosugars were used,12,18b,21
thus eliminating the need of any deprotection step before
biological evaluation. Another major concern was to drive the
thiol–ene coupling reactions to 100% conversion using only
stoichiometric amounts of thiol partners relative to the alkene
pendant side chains, in order to avoid complex product isola-
tion. A careful optimization of the TEC process using 1-thio-b-D-
glucose (bGlcSNa) as model thiosugar (see ESI† for details) led to
the following conditions: bGlcSNa/1 M HCl (1.1 eq. per alkene
moiety), 20 mol% of 2,2-dimethoxy-2-phenylacetophenone (DPAP)
as photoinitiator,22 overnight irradiation in water using a pyrex
filter. After irradiation, the photoinitiator was removed from the
crude by extraction with dichloromethane. A simple purification
of the glycocluster was then performed using a C18 SPE cartridge.
While the glycopeptoid was retained on the stationary phase,
washing with one volume of water eliminated the remaining
thioglucose and NaCl resulting from thiolate neutralization. Then
elution with one volume of methanol and successive vacuum
evaporation provided the multivalent glycopeptoid in pure form.
The photoclick-optimized conditions were then applied to various
linear and cyclic scaffolds using 1-thio-b-D-glucose and two other
thiosugars of interest for lectin recognition: 1-thio-b-D-galactose
and 1-thio-a/b-D-mannose. The dimeric and tetrameric glycoclusters
10–18 were thus obtained in good to excellent yields (Table 2).
The binding affinities of selected thioglycoclusters were
evaluated towards two soluble lectins produced by Pseudomonas
aeruginosa and Burkholderia cenocepacia which are pathogenic
bacteria involved in opportunistic infection in patients with
immunosuppression or in life-threatening lung infection in
cystic fibrosis patients.23 LecA (also named PA-IL) is a cytotoxic
galactose-specific lectin from P. aeruginosa involved in bacterial
adhesion and biofilm formation.24 The X-ray structure of the
lectin/galactose complex reveals a tetrameric quaternary struc-
ture with the presence of a bridging calcium ion in the binding
site (Fig. 2).25 BC2L-A is one of the four soluble lectins identified
in B. cenocepacia.26 This mannose specific lectin shows a dimeric
arrangement with a binding site involving two calcium ions.
The study of the interaction between glycoclusters 15–18
(Fig. 3) and these two lectins was performed by isothermal
Table 1 Structures of linear peptoid scaffolds
Scaffold
n
PGC
PGN
R1
R2
Global yielda (%)
1
2
3
4
5
6
7
1
1
1
1
1
2
2
OtBu
OtBu
OMe
OtBu
OMe
OMe
OtBu
H
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
iPr
iPr
Allyl
Allyl
42
29
34
36
25
32
40
Ac
Ac
H
Ac
Ac
H
a
Yield calculated for 7 to 8 steps from tert-butyl acrylate or methyl
acrylate. See ESI for experimental conditions.
was achieved by a solid-phase submonomer approach using
acetylated sugars bearing at the anomeric position a thioethyl
amino linker.19 Obviously, the multivalent TEC ligation on already
built peptoid scaffolds represents the most convergent way to
multivalent thioglycopeptoids. The present study combines an
efficient synthetic process for the preparation of alkene-
functionalized linear and cyclic peptoids with multivalent thiol–
ene coupling to access thioglycoclusters ready for biological
evaluation towards bacterial lectins. To reach this objective,
gram-scale syntheses of linear b- and alternated a,b-peptoids
carrying allyl side chains were efficiently performed thanks to a
solution-phase methodology using volatile amines developed
previously in our lab and avoiding intermediate purification
steps.18a Briefly, the peptoid residues are created in two steps by
acylation of the N-terminus of the peptoid, followed by reaction of
the acylated intermediate (a bromoacetamide for an a residue or
an acrylamide for a b residue) with the desired volatile amine
(allylamine or isopropylamine in the present study). Linear peptoid
scaffolds were thus obtained from tert-butyl or methyl acrylate, in
an iterative manner with single final column chromatography
purification, the intermediates being merely purified by filtration
and/or evaporation (Table 1). The cyclic peptoid scaffolds 8 and 9
were efficiently formed by cyclisation of their linear precursors 4
and 7 under EDCI/HOBt conditions after TFA deprotection of the
C-terminus (Scheme 1).20 Following this approach, ten linear or
cyclic b- or a,b-peptoids with 2 or 4 ligation sites and different
capping groups have been synthesised to highlight the scope of
photoinduced thiol–ene coupling with 1-thiosugars. The TEC
process was optimized following as much as possible click
Table 2 Linear and cyclic peptoid glycoclusters
Entry
Scaffold
Sugara
Glycocluster
nb
Yield (%)
1
2
3
4
5
6
7
8
9
3
5
6
8
9
3
9
9
9
1-Thio-b-D-Glc
1-Thio-b-D-Glc
1-Thio-b-D-Glc
1-Thio-b-D-Glc
1-Thio-b-D-Glc
1-Thio-b-D-Gal
1-Thio-b-D-Gal
1-Thio-a-D-Man
1-Thio-b-D-Man
10
11
12
13
14
15
16
17
18
4
2
4
2
4
4
4
4
4
90
90
81
68
73
76
66
66
67
Scheme 1 Cyclisation. Key: (a) TFA/CH2Cl2 then (b) EDCI (3.0), HOBt
(3.0), Et3N (6.0), CH2Cl2, r.t.
a
b
Sodium salt. Valency.
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(Kd 41 mM)28 showing that replacement of oxygen by sulfur has
no influence on the binding affinity (Table 3). Both linear and
cyclic tetrameric glycoclusters 15 and 16 displayed greatly
improved affinity compared to the monovalent b-D-GalSEt. The
binding stoichiometry (n) for both compounds demonstrates a
1 : 4 glycocluster/lectin ratio, i.e. the implication of the four
thiosugars in the binding event as previously obtained with a
cyclic b-tetrapeptoid as scaffold.28 The cyclic thioglycopeptoid 16
with a Kd value of 97 nM is in the range of the most potent LecA
ligand identified to date.29 As expected, the more rigid cyclic
peptoid 16 presents an entropy barrier lower than those of the
linear ones, and the 2 KJ molÀ1 difference in the TDS entropy
contribution explains the higher affinity for the cyclic molecules,
since both compounds display the same enthalpy of binding.
For the dimeric BC2L-A lectin, the ITC values of the monovalent
ligand a-D-ManSEt were shown to be almost identical to those
measured for a-D-ManOMe (Table 3).26a The b-thiomannoside
bound with almost equivalent affinity (Kd 9.6 mM). For both
compounds, analysis of the thermodynamic contributions
indicates a favourable entropy term, which is unusual in
protein–carbohydrate interaction, but previously observed in
this family of lectins and attributed to the presence of two
calcium atoms in the binding site.30 The cyclic tetrameric
glycopeptoids 17 and 18, differing only by the a/b-anomeric
configuration, gave improved avidity for BC2L-A compared to
their monovalent counterparts (see ESI,† Fig. S1). Particularly,
the 1-thio-a-D-mannoside cluster 17 displayed a 204 nM dis-
sociation constant similar to that of a rigid dimannoside
compound recently published but with different binding thermo-
dynamics.26b The tetrameric cluster 17 gave a higher enthalpy but
together with a higher entropic cost. The stoichiometry and
enthalpy values indicate that 3 to 4 BCL2-A monomers are bound
to each cluster.
Fig. 2 Crystal structure of LecA/galactose complex (PDB code 1OKO)25
and BC2L-A/mannoside complex (PDB code 2VNV).26a Dashed lines
represent the distances between sugar ring oxygen atoms.
Fig. 3 Structures of thiogalactoside ligands 15 and 16 evaluated towards
LecA and thiomannoside ligands 17 and 18 evaluated towards BC2L-A.
titration microcalorimetry (ITC) (Table 3). This bioanalytical
The high efficiency of glycoclusters for binding to multi-
technique is particularly suited since it furnishes complete valent lectin is generally observed when the geometry is well
thermodynamics providing a general overview of the binding suited for chelating two neighbouring binding sites.28,29d, f In
process involved.27
the present case, the tetravalent mannosylated clusters cannot
Linear and cyclic tetrameric thiogalactoside glycoclusters 15 chelate the two binding sites of BC2L-A that are 40 Å apart
and 16 were evaluated towards LecA (Fig. 2). First, the binding (Fig. 2). Indeed, building peptoid models using the crystal
ability of LecA to the model ethyl 1-thio-b-D-galactopyranoside structure of the scaffold31 and extended conformation of the
was evaluated in order to assess the influence of anomeric mannosylated arms do not give extension larger than 20 Å
oxygen replacement by sulfur. Indeed, previous studies showed (see ESI,† Fig. S2). Therefore only aggregation can occur for
a tenfold higher affinity of aromatic thiogalactosides (Kd 6.3 mM) BC2L-A interacting with 17 and 18. Interestingly, the same
compared to a- or b-D-GalOMe (Kd 70 mM).5d The monovalent conclusion was reached for LecA, since the binding sites
ligand b-D-GalSEt gave ITC values similar to those of b-D-GalOMe are 30 Å away, and ligands 15 and 16 could not extend more
Table 3 Isothermal titration microcalorimetry (ITC) measurements for the binding of ligands b-D-GalSEt, 15 and 16 to LecA and ligands a-D-ManSEt,
b-D-ManSEt, 17 and 18 to BC2L-A. Standard deviations are indicated on experimentally derived values (at least two experiments)
Ligand
Valency
n
DH [kJ molÀ1
]
DG [kJ molÀ1
]
TDS [kJ molÀ1
]
Kd [mM]
Relative potency [b]
b-D-GalSEt
15
16
a-D-ManSEt
b-D-ManSEt
17
18
1
4
4
1
1
4
4
1 (fixed)
À31 Æ 7
À124 Æ 6
À25
À6
41.6 Æ 1.5
0.214 Æ 0.05
0.097 Æ 0.01
3.3 Æ 0.5
1
194
429
1
0.23 Æ 0.01
0.18 Æ 0.01
1.06 Æ 0.1
1.06 Æ 0.02
0.33 Æ 0.01
0.34 Æ 0.01
À38
À86
À124 Æ 10
À23.0 Æ 1
À40
À84
À31.3
À28.7
À38.2
À33.3
+8.3
À21.6 Æ 0.1
À108.5 Æ 2.6
À76.2 Æ 2.5
+7.1
9.57 Æ 0.05
0.204 Æ 0.001
1.45 Æ 0.3
0.3 (vs. a-ManSMe)
16 (vs. a-ManSMe)
6.6 (vs. b-ManSMe)
À70.3
À42.9
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