Sugar-modified foldamers as conformationally defined and biologically distinct glycopeptide mimics

Article abstract of DOI:10.1002/anie.201304239

To fold or not to fold? It is shown that attached sugars play a defining role in the conformations adopted by a pair of novel SAA-derived foldamers in water and that these differences are reflected in the contrasting interactions of these glycofoldamers with various biological targets. C green, O red, N blue, H gray; yellow oval=mannose. Copyright

Full text of DOI:10.1002/anie.201304239

Angewandte
Chemie
DOI: 10.1002/anie.201304239
Glycopeptide Foldamers
Sugar-Modified Foldamers as Conformationally Defined and Biolog-
ically Distinct Glycopeptide Mimics**
Aloysius Siriwardena,* Kiran Kumar Pulukuri, Pancham S. Kandiyal, Saumya Roy,
Omprakash Bande, Subhash Ghosh, Josꢀ Manuel Garcia Fernꢁndez, Fernando Ariel Martin,
Jean-Marc Ghigo, Christophe Beloin, Keigo Ito, Robert J. Woods, Ravi Sankar Ampapathi,* and
Tushar Kanti Chakraborty*
It is predicted that over half of all eukaryotic proteins are
glycosylated, and it is now well-established that co- and post-
translational modification of proteins with glycans can have
dramatic consequences on their folding, stability, and ulti-
mately their function.[1] Considerable effort has thus been
invested in delineating the impact of appended carbohydrates
on the conformational preferences of proteins and peptides in
solution and vice versa,[2] and also in understanding their
interactions with their cognate receptors.[3] These endeavours
are not straightforward, and success in rationalizing such
processes has been possible only in a handful of well-studied
cases.[4] Important insights into such questions have been
gleaned from the study of glycoconjugate mimetics, whose
interactions with cellular targets can impact a wide range of
physiological phenomena, including fertilization, immune
response, host–pathogen interactions, cell growth, and
tumor metastasis.[1] However, attempts to successfully corre-
late biological functions of structurally well-defined glyco-
peptides with their secondary structures have been relatively
sparse,[2–4] despite the importance of such targets in the quest
for carbohydrate-based therapeutics.[5]
origins of the preferred secondary structures and biological
activities of biopolymers.[7] Considering the endogenous and
therapeutic importance of glycoproteins, we were struck by
the dearth of reports describing the impact of glycosylation on
the secondary structures of peptide foldamers.[8] Appended
sugars in the two families of newly synthesized d-SAA-
derived glycofoldamers indeed play a defining role on the
preferred conformations of the peptide foldamer backbones
and, far less commonly, are seen to do so even in water.[9]
Furthermore, the differences in conformation manifested by
each glycofoldamers are shown to be mirrored in their distinct
and contrasting interaction with selected targets including the
lectin Concanavalin A (ConA)[10a] and the bacterium Escher-
ichia coli (E. coli).[10b]
The families of d-SAA-derived foldamers targeted for
investigation herein, annotated cis- and trans- in the text,
differ from one another in the configuration of the stereo-
center at C2 of the furanoid rings of their constituent d-SAA
moieties: those with the “2S” configuration designated cis-
foldamers, and those with “2R”, trans-foldamers (Scheme 1).
Previous work has shown that in organic solvents, cis-
foldamers adopt conformations reminiscent of a conventional
b-turn, whereas the secondary structures of trans-foldamers
are dependent on the substituent pattern of their constituent
furanoid rings.[11] The targeted families of d-SAA-based
Herein we examine the effects of appended sugar moieties
on the conformational behavior of peptide foldamers derived
from d-sugar amino acids (d-SAAs).[6] The study of foldamers
has in the past helped enlighten our understanding of the
[*] K. K. Pulukuri, Dr. T. K. Chakraborty
Medicinal & Process Chemistry Division
CSIR-Central Drug Research Institute
Lucknow 226031 (India)
Dr. F. Ariel Martin, Dr. J.-M. Ghigo, Dr. C. Beloin
Institut Pasteur, Unitꢀ de Gꢀnꢀtique des Biofilms
25 rue du Dr. Roux, 75724 Paris cedex 15 (France)
Dr. K. Ito, Dr. R. J. Woods
E-mail: chakraborty@cdri.res.in
The Complex Carbohydrate Research Center
The Department of Biochemistry and Molecular Biology
The University of Georgia, Athens, 30602 GA (USA)
P. S. Kandiyal, Dr. R. S. Ampapathi
Centre for Nuclear Magnetic Resonance, SAIF
CSIR-Central Drug Research Institute (India)
Lucknow 226031 (India)
Dr. R. J. Woods
The School of Chemistry, National University of Ireland, Galway
University Road, Galway (Ireland)
E-mail: ravi_sa@cdri.res.in
Dr. A. Siriwardena, Dr. S. Roy, Dr. O. Bande
Laboratoiredes Glucides, FRE-3517
Universitꢀ de Picardie Jules Verne, Amiens 80039 (France)
E-mail: aloysius.siriwardena@u-picardie.fr
[**] T.K.C., R.S.A., A.S., S.R., and O.B. acknowledge financial support
from the CEFIPRA-ICPAR. K.K.P. and P.S.K. are thankful to CSIR,
New Delhi, for financial support. A.S., S.R., and O.B. acknowledge
support from the CNRS. R.J.W. and K.I. thank the NIH (GM094919)
(EUREKA) and the Science Foundation of Ireland (08/IN.1/B2070)
for financial support. The SAIF-CDRI and the LG, Amiens are
thanked for analytical facilities. The authors wish to thank Profs I.
Huc (Bordeaux) and J. Jimꢀnez-Barbero (Madrid) for their critical
reading of the manuscript. This is CSIR-CDRI communication No.
8490.
Dr. S. Ghosh
Organic Chemistry Division III
CSIR-Indian Institute of Chemical Technology
Hyderabad 500 007 (India)
Dr. J. M. Garcia Fernꢁndez
Instituto de Investigaciones, Quꢂmicas(IIQ)
CSIC-Universidad de Sevilla
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304239.
Amꢀrico Vespucio 49, 41092 Sevilla (Spain)
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by a CuI-catalyzed Huisgen click cycloaddition[13] to give the
corresponding conjugates 2a,b or 3a,b, respectively
(Scheme 2). This click conjugation method has found appeal
previously in neoglycopeptide assembly, where the triazole
moieties themselves can impact physiochemical properties or
biological activities of the resulting glycoconjugates.[14]
The data derived from NMR spectroscopy were used to
establish the conformational preferences of the peptide
foldamers, as this technique can provide discrete structural
1
information at the atomic level.[2–4] The H NMR spectra of
foldamers 1a,b and their clicked analogues 2a,b in CDCl3
feature sharp resonances and well-resolved amide proton
signals, suggesting the presence of predominantly well-
defined folded structures in solution. The downfield chemical
shifts observed for the amide protons in the spectra of 1a,b
and 2a,b further suggest their participation in internal
hydrogen bonding (H-bonding), a feature that is also
supported by the minimal perturbation of these signals
upon titration in 33% of [D6]DMSO (v/v).[12] For peptide
foldamers 1a and 2a, the small changes in chemical shifts
(Dd), observed for the NH2, NH3, and NH4 in solvent
titration studies, and the invariance of their chemical shifts in
variable concentration studies, are also consistent with the
participation of these protons in intramolecular H-bonding.[15]
The presence of sequential nOe cross-peaks between
1
2
2NH$ C6H(pro-R), 1C3H(pro-S)
,
3NH$ C6H(pro-R)
, ,
2C3H(pro-S)
3
3
4NH$ C6H(pro-R), and C3H(pro-S) in the ROESY spectrum of
foldamer 1a (Scheme 3) corroborates the participation of
NH2, NH3, and NH4 in H-bonding, consistent with a 10-
membered turn network implicating NH(i)-CO(i-2).[12] Fur-
thermore, the medium-intensity nOes observed between
1
1
4
2
2
3NH$ C3H(pro-R), C3H(pro-S) and NH$ C3H(pro-S), C3H(pro-R)
suggest that foldamer 1a adopts a compact secondary
structure. The clicked foldamer analogue 2a afforded iden-
tical data to its precursor 1a, suggesting that these two
compounds share related secondary structures.
Scheme 1. Representation of d-SAA based hybrids.
hybrid peptides, 1a and 1b, were assembled following
a convergent strategy from the corresponding monomeric d-
SAA precursors 6a and 7a (for 1a) or 6b and 7b (for 1b),
respectively. The required monomeric d-SAA building blocks
were conveniently obtained from the same starting sugar, 2-
deoxy-d-ribose.[12]
The NMR spectra of cis-glycofoldamer 3a, featuring two
acetylated mannose units, display similar nOes and H-
bonding networks as seen for 1a when recorded in CDCl3.
However
a very weak medium-range nOe between
2
4NH$ C6H(pro-R) observable in the ROESY spectrum of cis-
analogue 3a (Figure 1) indicates the presence of an additional
bend around the second H-bonding, which is also suggested
N-Boc deprotection of 6a and saponification of the
methyl ester function of 7a gave precursors 8a and 9a,
respectively, which when condensed under standard solution-
phase peptide coupling conditions gave smoothly the corre-
sponding cis-d-SAA dimer 10a. The dimer 10a could be
deprotected at either ends to give the precursors 11a and 12a
which, when reacted together (standard peptide coupling
conditions), gave the target cis-d-SAA based tetramer 1a
(Scheme 2). An identical reaction sequence starting from the
trans-d-SAA monomers 6b and 7b allowed the straightfor-
ward assembly of the corresponding trans-d-SAA derived
tetramer 1b (Scheme 2). It was envisaged that the azido
functions, thus integrated, would subsequently allow ready
conjugation of selected partners at precise positions along
each d-SAA-derived backbone post-assembly. As expected,
reaction of either 1a or 1b with either non-sugar or sugar
partners armed with propargyl functions proceeded smoothly
3
1
by the absence of the nOe between NH$ C3H(pro-S) present
in 1a. Titration studies carried out by sequential addition of
33% [D6]DMSO(v/v) to 3a gives a Dd value for NH that is
3
0.26 ppm greater than those observed for the 2nd and 4th d-
SAA amide protons and further supports that in 3a local
3
distortions at NH occur. Taken together, these observations
suggest that 3a tends towards a higher-order structure than
adopted by foldamer 1a.
It was critical that the glycofoldamers would be soluble in
water once deprotected, so that their biological evaluation
might be undertaken. That these glycofoldamers would
maintain distinct secondary structures in water was also
imperative. Although short linear d-SAA-based backbones
(non-glycosylated) are predisposed towards defined secon-
dary structures in organic solvents,[9] these are invariably
disrupted upon deprotection.[16] We were nevertheless hope-
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these amide protons in H-bonding. The
data taken together is consistent with the
cis-glycofoldamer 4a existing predomi-
nantly in a 16-membered H-bonded turn
structure involving 3NH$Boc-CO and
1
4NH$ CO.
The deacetylated/debenzylated cis-
glycofoldamer 5a, studied in 94%
H2O + 6% D2O, showed an almost iden-
tical nOe pattern and H-bonding net-
work as that observed for 4a, suggesting
similar secondary structures for both. As
far as we are aware this is the first high-
order 16-membered turn structure
observed in water for any foldamer.
The conformational switch evidenced
for the cis-glycofoldamers 4a/5a is
driven uniquely by their appended man-
nosyl moieties and are not observed for
the foldamer 2a, which features an
alternate aliphatic ester-appended back-
bone.
It is noteworthy that NMR data
recorded for the members of the trans-
foldamer family, 1b–3b, are very similar
to those of their cis-counterparts, sug-
gesting that they share related confor-
mational properties. For example, the
trans-foldamer 1b displayed sequential
nOe peaks between (i)NH$(iꢀ1)C5H,
(i)NH$(iꢀ1)C6H(pro-S) in its NMR spec-
trum together with those characteristic
of a 10-membered H-bonded conforma-
tion for (i)NH$(iꢀ2)CO similar to that
observed for the cis-foldamer 1a. Sol-
Scheme 2. Synthesis of SAA-based hybrids. Reagents and conditions: i) 30% TFA in CH2Cl2,
08C–RT, 3 h; ii) LiOH, THF/MeOH/H2O (3:1:1), 08C–RT, 1 h; iii) 1-ethyl-3-(3-dimethylaminopro-
pyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), diisopropylethylamine
(DIPEA), CH2Cl2, 08C–RT, 12 h; iv) sodium ascorbate, CuSO4·5H2O, methyl propiolate, RT,
CH2Cl2, 12 h, 79%; v) Sodium ascorbate, CuSO4·5H2O, 13, EtOH, H2O, microwave, 808C,
5 min, 84–86%; vi) NaOMe, MeOH, RT, 2 h, Amberlite 120H+, 91–94%; vii) H2, Pd-C, MeOH,
RT, 12 h, 70–76%.
Scheme 3. Characteristic nOes and H-bonding pattern of the 10-
membered repeat structure of 1a in CDCl3.
ful that the glycofoldamers synthesized herein, once depro-
tected, would behave similarly to short natural glycopeptides
in water, in which attached carbohydrates have been demon-
strated to stabilize secondary structures or compact confor-
mations.[17] Indeed, deacetylation or deacetylation/debenzy-
lation of cis-glycofoldamer 3a afforded the corresponding
analogues 4a or 5a, respectively, which proved to be soluble
in either methanol (4a) or water (5a).
The NMR data for 4a in CD3OH features a sequence of
i$i + 2 nOes along with those nOes observed in the spectra of
1a and 3a. The medium-range nOes between (i)NH$(i-
2)C6H(pro-R) and (i)NH$(iꢀ2)C3H(pro-S) (Scheme 4 and
Figure 1. Expanded ROESY spectrum of 3a in CDCl3 (ca. 9 mm, 300 K).
2
1
1
2
The nOes NH$ C6H(pro-S), 2NH$ C6H(pro-R), 4NH$ C6H(pro-R)
,
Figure 2) identified in the spectrum of 4a for the 3rd and
4th residues, with the data of solvent exchange studies and
minimal temperature dependencies, confirms participation of
3
1
3
2
4NH$ C6H(pro-R), 2NH$ C5H, 4NH$ C5H, and 3NH$ C5H are marked
as 1–7.
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Scheme 4. Characteristic nOes and H-bonding pattern of the 16-
membered helical turn structure of 4a in CD3OH.
Figure 3. 10- and 16-membered cis-d-foldamers and cis-d-glycofoldam-
ers. H-bonded average MD structure of A) 1a, B) 3a, C) 4a, and
D) 5a.
conformations range from 5.45 ꢀ to 9.40 ꢀ), and 6.58 ꢀ for
the trans-compound, 5b (20 least-energy conformations vary
from 5.25 ꢀ to 8.19 ꢀ) respectively.
We were curious to establish whether or not the mannosyl
residues in glycofoldamers 5a and 5b interacted with selected
biological targets differently, despite the fact that the average
distance between these residues differs by less than 0.2 ꢀ
(from MD calculations). Any difference in binding between
5a and 5b was anticipated to provide additional insights into
the impact of foldamer conformational properties. The
protein ConA, which is known to bind mannopyranosyl
moieties preferentially, and the bacterium, E. coli in which the
lectin FimH contributes specifically to bladder colonization
through binding to terminal a-d-mannosyl units that are
present on glycoproteins such as uroplakins, were selected for
examination.[18,10b]
The predisposition of glycofoldamers 5a and 5b to bind
our targets was initially probed in a superimposition study in
which the structures of the glycofoldamers (determined
experimentally) and those of the proteins were kept rigid.[19]
Each of the two mannosyl residues in 5a and 5b were then
superimposed onto the mannosyl residues of ligands[12]
complexed in the binding pocket of ConA or that of FimH
(PDB codes: 1CVN, 2VCO), respectively. This resulted in two
possible poses for the pair of glycofoldamers with each
protein, all of which were evaluated for steric collisions.
Significant steric clashes were observed between ConA and
both 5a and 5b for all but one pose.[12] The superposition of
glycofoldamers 5a and 5b onto the Man3GlcNAc2 in FimH
also resulted in unacceptable interactions.[12] The preliminary
study indicates that some level of induced fit would be
Figure 2. Expanded ROESY spectrum of 4a in CD3OH (ca. 8 mm,
1
2
1
4
2
300 K). The nOes 2NH$ C6H(pro-S), NH$ C6H(pro-R), NH$ C6H,
1
2
3
1
3
3NH$ C6H(pro-R), 4NH$ C3H(pro-S), NH$ C3H(pro-S), 4NH$ C6H(pro-R)
,
3
2
4NH$ C5H, and 3NH$ C5H are marked as 1–9.
vent titration studies further supported the adoption of a 10-
membered H-bonding pattern by 1b.[12] Likewise, the trans-
glycofoldamers 2b and 3b also exist in a stable 10-membered
H-bonded conformation similar to that observed for the
corresponding cis-glycofoldamers 2a and 3a. However, care-
ful observation of the deacetylated, or deacetylated/debenzy-
lated trans-glycofoldamers, 4b and 5b respectively, showed
that they do not form the higher-order structures observed in
their cis-counterparts 4a and 5a, but rather maintain the
conformational preferences adopted prior to their being
appended with sugar moieties.
Restrained molecular dynamics (MD) studies were car-
ried out using experimental distance and torsional constraints
derived from nOe volume integrals and vicinal coupling
constants (3J), respectively. The average structures of the 5 ns
MD run of each cis-glycofoldamers are presented in Figure 3.
The average distance between the anomeric carbons of
mannosyl residues, as calculated from the structure ensem-
bles, is 6.73 ꢀ for the cis-analogue, 5a (20 least-energy
4
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expected for binding of the glycofoldamers 5a or 5b with
either of the selected targets.
notion that subtle differences in solution conformation, and it
is likely that dynamics preferences should indeed have
consequences on the underlying biology of natural glycopep-
tides even when these might be structurally closely related.[2–4]
An enzyme-linked lectin assay (ELLA)[20] providing
information on binding affinity between the sugar ligand
and a single CRD in the lectin indeed confirms that both
glycofoldamers are recognized by ConA, with the cis-
compound, 5a giving an IC50 (inhibitory concentration 50)
some 1.3 fold lower (IC50 = 347 ꢁ 10 mm) than its trans-
counterpart 5b, (IC50 = 440 ꢁ 10 mm).[12] However, nearly
four- to sixfold affinity enhancement was found for Man3
(IC50 = 75 ꢁ 6 mm), which supports the hypothesis that
induced fit would be required for an increase in binding of
either glycofoldamers with ConA, as suggested also by the
findings of the superimposition studies. Peptide glycofoldam-
ers 5a and 5b were also evaluated as inhibitors for FimH-
expressing K-12 E. coli adhesion.[21] In this study, the cis-
analogue 5a gave an inhibition titer (IT) fourfold lower (IT=
0.087 mm) than the trans-compound 5b (IT= 0.35 mm) in the
yeast agglutination assay.[12] The IT was considered as the
lowest compound concentration able to inhibit agglutination.
Likewise, both glycofoldamers were seen to reduce the
binding of E. coli to T24 bladder cells, the cis-glycofoldamer
5a giving an IC50 of some 2.2-fold lower (IC50 = 0.02986 mm)
than its trans-counterpart 5b (IC50 = 0.06621 mm). Binding to
an E. coli strain not expressing FimH was not seen.[12] The
differences observed between glycofoldamers 5a and 5b, in
assays with both ConA as well as E. coli, are consistent with
their contrasting conformational preferences. The origin of
these differences may at present only be conjectured upon.
The data presented is the first demonstration that
appended carbohydrates can have a defining influence on
the structural preferences of d-SAA-derived foldamer back-
bones in water. Of particular significance is the observation
that the grafted mannoside moieties provoke a conforma-
tional switch in the cis-foldamer backbone (and not in its
trans-foldamer counterpart) from a 10-membered H-bonded
turn structure, when not appended with sugars, to an
unprecedented 16-membered helical one when mannosyl
units are grafted. The variations are seen to be exquisitely
dependent on the particular backbone to which sugars are
appended and is consistent with a scenario in which the
mannosyl units modulate the backbone torsional preferences
of a given foldamer as defined by its backbone stereochem-
istry (cis- or trans-) and amplified by variations in its
constituent d-SAA furanoid (2R- or 2S-) conformations.
Our findings mirror those of Imperiali et al.,[22] who observed
a chitobiose-driven conformational switch of a short peptide
backbone and further showed by NMR that this was not due
to any observable interaction between the peptide backbones
and their constituent sugar moieties.[2,22] Likewise, in neither
glycofoldamer 5a or 5b are any interactions observable
between the peptide backbone and the constituent mannosyl
residues by NMR spectroscopy.
Received: May 17, 2013
Revised: July 2, 2013
Published online: && &&, &&&&
Keywords: neoglycopeptides · protein–
.
carbohydrate interactions · restrained molecular dynamics ·
solution conformational preferences · glycofoldamers
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Of particular significance is the demonstration that the
interactions of the cis- and trans-glycofoldamers 5a and 5b
with both the lectin ConA and the bacterium E. coli are
distinct, suggesting that these differences may have their
seeds in the underlying conformational preferences of this
pair of neoglycopeptides. These data further confirm the
[12] See the Supporting Information.
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Angewandte
Chemie
Communications
Glycopeptide Foldamers
To fold or not to fold? It is shown that
attached sugars play a defining role in the
conformations adopted by a pair of novel
SAA-derived foldamers in water and that
these differences are reflected in the
contrasting interactions of these glyco-
foldamers with various biological targets.
C green, O red, N blue, H gray; green
oval=mannose.
A. Siriwardena,* K. K. Pulukuri,
P. S. Kandiyal, S. Roy, O. Bande,
S. Ghosh, J. M. Garcia Fernꢁndez,
F. Ariel Martin, J.-M. Ghigo, C. Beloin,
K. Ito, R. J. Woods, R. S. Ampapathi,*
T. K. Chakraborty*
&&&& — &&&&
Sugar-Modified Foldamers as
Conformationally Defined and
Biologically Distinct Glycopeptide
Mimics
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!