New Paradigm in NKT Cell Antigens: MCS-0208 (2-(Hydroxymethyl)phenylthio-phytoceramide) – an Aryl-Phytoceramide Compound with a Single Hydroxyl Group Stimulates NKT Cells

Article abstract of DOI:10.1002/cmdc.202000992

Natural Killer T (NKT) cells play an important role in the immune response and can be activated by glycolipids presented by CD1d protein. We present MCS-0208, an unprecedented arylthioether-phytoceramide able to induce potent invariant NKT (iNKT) cell activation, notably when tested in human iNKT cells. This arylsphingolipid analog has a simple phenyl group containing a single hydroxyl substituent as a surrogate of the sugar ring. The phenylthioether structure contrasts with α-galactosylceramide (1), the prototypical glycolipid used to induce iNKT cell stimulation, where the galactose 2’-OH and 3’-OH substituents are accepted as the minimal footprint and considered critical for NKT T cell receptor (TCR) recognition. A computational study supports the recognition of aromatic compound by the CD1d and TCR proteins as radically new structures for NKT cell stimulation.

Full text of DOI:10.1002/cmdc.202000992

Accepted Article
Title: New paradigm in NKT cell antigens: MCS-0208 (2-
(Hydroxymethyl)phenylthio-phytoceramide) an aryl-
phytoceramide compound with a single hydroxyl group stimulates
NKT cells
Authors: Amadeu Llebaria, Roser Borràs-Tudurí, Anna Alcaide,
Sandrine Aspeslag, Lorena Usero, Carme Serra, Carme
Roura-Mir, and Dirk Elewaut
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To be cited as: ChemMedChem 10.1002/cmdc.202000992
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0
1/2020

ChemMedChem
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COMMUNICATION
New paradigm in NKT cell antigens: MCS-0208 (2-
(Hydroxymethyl)phenylthio-phytoceramide) an aryl-
phytoceramide compound with a single hydroxyl group
stimulates NKT cells
[
a],ϯ
[a],ϯ
[b,c]
[d]
[a]
Roser Borràs-Tudurí , Anna Alcaide , Sandrine Aspeslag , Lorena Usero , Carmen Serra ,
[d]
[b,c]
[a]
Carme Roura-Mir , Dirk Elewaut , Amadeu Llebaria*
[
a]
Dr. R. Borràs-Tudurí, Dr. A. Alcaide, Dr. C. Serra an Dr. A. Llebaria*
Medicinal Chemistry and Synthesis (MCS) Laboratory
Institut de Química Acançada de Catalynya (IQAC), Consejo Superior de Investigaciones Científicas (CSIC)
C/ Jordi Girona 18-26, 08034 Barcelona, Spain.
E-mail: amadeu.llebaria@iqac.csic.es
Dr. S. Aspeslag, Dr. D. Elewaut
Unit for Molecular Immunology and Inflammation
VIB-Center for Inflammation Research
Ghent, Belgium
Dr. S. Aspeslag, Dr. D. Elewaut
Department of Internal Medicine and Pediatrics
Ghent University
Ghent, Belgium
Dr. L. Userio, Dr. C. Roura-Mir
Laboratori d´Immunologia Cel·lular,
Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona
Bellaterra, 08193 Barcelona, Spain
[
[
[
[
b]
c]
d]
ϯ
]
This authors contributed equally
Supporting information for this article is given via a link at the end of the document
Abstract: Natural Killer T (NKT) cells play an important role in the
immune response and can be activated by glycolipids presented by
CD1d protein. We present MCS-0208 an unprecedented
arylthioether-phytoceramide able to induce potent invariant NKT
a very potent activity and induces both Th1 and Th2 opposite
responses from NKT cells with several undesired effects.
Another undesirable effect of GalCer was its overstimulation
leading to an unresponsiveness state of the cells. Therefore,
plenty of studies were conducted to modify the structure of
GalCer in order to optimize its physicochemical and biological
properties. Hundreds of new compounds were synthesized and
biologically studied concluding which part of the GalCer
structure has an impact on the strength or the type of response
(Figure 1). In general, most chemical efforts were focused on
the galactose moiety and the lipid chains. The sugar was
extensively studied exploring both - and -linked glycolipids,
the configuration of the hydroxylated carbons (introducing
glucose, mannose or other sugars) and hydroxyl substitution or
fuctionalization. There is a general agreement on the critical
importance of 2’-OH and 3’-OH for CD1d recognition while the
modification on other parts of the galactose can be somehow
modified to modulate the interaction with the T cell receptor
(iNKT) cell activation, notably when tested in human iNKT cells. This
arylsphingolipid analog has a simple phenyl group containing a
single hydroxyl substituent as a surrogate of the sugar ring. The
phenylthioether structure contrasts with -galactosylceramide (1),
the prototypical glycolipid used to induce iNKT cell stimulation,
where the galactose 2’-OH and 3’-OH substituents are accepted as
the minimal footprint and considered critical for NKT T cell receptor
(TCR) recognition. A computational study supports the recognition of
aromatic compound by the CD1d and TCR proteins as radically new
structures for NKT cell stimulation.
During the past two decades an extensive research was done
on designing, synthesizing and evaluating new -
[
1]
galactosylceramide (GalCer) derivatives . This galactose -
linked to a phytoceramide lipid was found during a screening of
anticancer agents of marine sponge extractions showing the
(
TCR) and, as a result, modulate the NKT cell response. The
other broadly studied part of the GalCer was the lipid chains,
[3,4]
exploring in both tails the length impact , ramification or
[
2]
induction of promising, potent and antitumor response . After
this finding, intensive efforts were directed to decipher the
mechanism of action of this compound resulting in the
identification of Natural Killer T (NKT) cells, a new subtype of
lymphocytes with Natural Killer (NK) cells and T lymphocytes
characteristics. Another important finding was that the particular
T cell receptor was restricted to CD1d-antigen complex. CD1d is
a non-classical MHC-class I that recognizes and presents lipid
antigens and in particular glycosphigolipid derivatives, instead of
peptides. The prototypical NKT cell stimulator GalCer, displays
substitution, and the introduction of other groups such as
[5–8]
[9]
aromatic rings , polar groups or halogens. Recently it was
published a new derivative able to bind covalently to the CD1d
[10]
antigen binding groove, increasing ligand affinity and inducing
a Th2 polarizing activity.Main Text Paragraph.
1
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[
11,12,14]
modulators
, some new thiosugar derivatives from our
chemical collection were screened as candidates for NKT cell
[
13]
[13]
[13]
modulation (compounds 6 , 7 and 8 in Figure 3). These
compounds presented a chemical structure related to or similar
to -glucosylceramide 5 (Figure 2), which was postulated as
[
15]
endogenous ligand candidate
at the time of this work was
[
16,17]
started however it was finally refused
.
Figure 3. Chemical structure of new -S-Glucosylceramide derivatives.
Immunostimulator potency of these compounds was measured
by IL-2 production of splenocites from Balb-6 mice in vitro.
Product 6 and 8 induced low levels of IL-2 secretion only
comparable to that of vehicle (Figure 4). Only compound 7
showed a slightly higher amount of cytokine secretion at the
highest dose (1000 ng/mL).
Figure 1. General overview of GalCer chemical structure and the impact of
each part in the biological response modulation.
Our group studied non-glycosidic compounds such as
aminocyclitol-ceramide
derivatives
HS44
and
HS161,
(
compounds 3 and 4 in Figure 2), showing high levels of
[
11,12]
cytokine prodution and anticancer in vivo activity
.
Figure 4. In vitro IL-2 secretion upon NKT cell stimulation with -S-GlcCers.
Splenocites were cocultured with each compound in triplicate. Error bars
indicate SD values.
Considering that -S-GalCer (2), the S-linked analogue of
Figure 2: Chemical structure of some aGalCer derivatives.
[18]
GalCer (1), was inactive when tested in mice cells, the low
levels of cytokine production of our new compounds were not
surprising. Moreover the lack of activity in the synthesized -
thioglucosylceramide analogues 6, 7 and 8 could not be entirely
attributed to the -configuration of the sugar moiety and other
factors like the length of the N-acyl chain and its degree of
Taking advantage of our group background on the chemical
synthesis of great diversity of sphingosine and
phytospgingosine derivatives in several fields from inhibitors of
a
[
13]
sphingolipid-metabolizing
enzymes
to
NKT
cell
2
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saturation, or the fact that these analogues are S-glycosides,
should be considered. Taking into account that compound 7 was
more active than the O-linked analogue -GlcCerd18:1-C24:1
[
16,17]
(
5)
, we decided to explore the NKT activity of our chemical
library of non glycosidic ceramide-derivatives with totally
different “polar” heads non-sugar related such as compounds
[
13]
[13]
[13]
[19]
9
, 10 , 11 and 12 (Figure 5). Moreover, being aware of
the importance of the acyl chain length, MCS-0208 (13, Figure
) was synthesized with the same ceramide skeleton as
GalCer (see Supporting Info for chemical details). To this
5

purpose, initial assays at the highest dose (1000 ng/mL) were
performed in vitro with splenocites from Balb-6 mice (Figure 6).
Figure 6. In vitro IL-2 secretion induced by sphingolipid analogues at 1000
ng/mL. Splenocites from BL6 mice were cocultured with each compound in
triplicate. Error bars indicate SD values.
In order to compare the potencies of the new ArCer with the -S-
GlcCer family, we synthesized compound 14 (Figure 7), a -S-
GlcCer with the same ceramide skeleton than MCS-0208 (13),
and they were evaluated together with a dose response of our
new hit compound. Interestingly, MCS-0208 (13) showed
consistent dose responses, and compound 14 was 2-fold less
active than MCS-0208 (13) at the same dose in spite of the
presence of the thiosugar (Figure 7).
Figure 5. Chemical structure of new ArCer family.
The in vitro experiments showed that most of the compounds of
this set did not activate iNKT responses in a meaningful manner
with the only exception of MCS-0208 (13) that showed stronger
induction of IL-2 secretion, but it was not as active as GalCer,
used as reference compound (Figure 6). It is important to
highlight the results of this new family of thioaryl-ceramides
(
ArCer). The NKT activity of MCS-0208 (13) was rather
unexpected because the structure of the group attached at
position 1 of the ceramide skeleton is very different from any
sugar mimetic. Furthermore, the other analogues with closer
structures to MCS-0208 (13), such as compounds 9, 10, 11 or
12 induced lower levels of IL-2 secretion. The main difference
was on the N-acyl chain length what was in the established
structural effects of the N-acyl groups required for CD1d
recognition. In same line of Structure-Activity studies, the short
[
2]
acyl chain was related to Th2 polarized activity what could
explain the lower levels of IL-2 (a cytokine included among Th1
ones) of compounds 9 to 12.
Figure 7. Comparative in vitro IL-2 secretion of ArCers and compound 14.
Splenocites from BL6 mice were cocultured with each analogue in triplicate.
Error bars indicate SD values.
3
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In view of these results, it was evident the interest in going
further and test the activity of compounds 7, MCS-0208 13 and
14 in vivo. Although it was not expected to reach similar
GalCer cytokine production levels, we were more interested in
evaluating the activity of the new MCS-0208 (13) compared to
other weak agonists with glycosylated ceramide structures. Thus,
lipids were tested in vivo and were administrated
intraperitoneally (5ug) in PBS to BL6 and 18-/- mice and
cytokine secretion was measured on mice sera by ELISA assay
(
IL-4 at 4 hours and IFN- at 16 hours) using GalCer as a
positive control. In vivo assays confirmed our in vitro results
showing an agonist profile for all three compounds, but
moreover confirmed that MCS-0208 (13) was a stronger agonist
than -S-GlcCer’s 7 and 14 (Figure 8). Interestingly, MCS-0208
(
13) was more active than its corresponding thiosugar analogs 7
and 14, and in all cases a Th1 polarization profile was observed,
with higher production of IFN- than IL-4. In addition MCS-0208
(
13) showed the strongest polarization profile.
Figure 9. A) In vitro TNF production of human NKT cells. B) In vitro IFN-

and IL-4 production of human NKT cells. Purified iNKT from human blood
were cocultered with pre-loaded transfected B-cells with each antigen in
triplicate. Error bars indicate SD values.
To further understand the activity of this unprecedented family,
some computational studies were done to explore how this
compound could interact with CD1d and the TCR. Initial docking
studies were carried out using crystal structure of our potent
aminocyciltol HS44 (3) and mouse proteins (PDB code:
[
14]
[20]
3
RTQ ). Protein was prepared following Protein Preparation
[
21]
protocol from Schrödinger
,
the corresponding grid was
centered to the polar head of the aminocyclitol assuming a
similar binding mode of the long lipid chains. Due to the high
number of rotatable bonds and to speed up the calculation,
truncated ligands and positional constraints were used to
properly locate each compound into the CD1d cavity and leaving
the aromatic moiety unconstrained (or the aminocyclitol moiety
of HS44 (3) as positive control). This experiment was repeated
10 times to have a good average of potential preferable binding
mode. These experiments suggest a binding mode for MCS-
Figure 8. In vivo results from BL6 mice injected i.p. Cytokine levels were
measured by ELISA assays. Error bars indicatge SD values.
As divergent results in mice and human NKT stimulation have
been reported for some compounds, we next tested MCS-0208
(
13) in human NKT cell stimulation assays. MCS-0208 (13)
induced a TNF production similar to that of aGalCer (Figure 9
A) suggesting a similar NKT cell stimulation ability and a
promising potency. To further explore this hypothesis, IFN- and
IL-4 cytokines levels were measured. At 10ng/mL our compound
showed similar IFN- levels than aGalCer however significant
lower levels of IL-4 were detected, pointing to a marked Th1
biased response. These results were unexpected considering
the low functionalization of the aromatic ring and therefore the
low number of potential contacts of the antigen with the contact
surface of CD1d and TCR proteins.
0
208 (13) with the aromatic ring in parallel to the carbohydrate
ring however slightly closer to CD1d than the sugar moiety.
Regarding to the only hydroxyl group from MCS-0208 (13), we
postulate that it could occupy a similar space to those occupied
by the 2’OH and 3’OH of the aminocyclitol (or the sugar mimetic
in any case). This binding mode could allow the interaction of
this exclusive polar group with two residues essentially involved
in the ternary complex formation: Gly96 on the TCR a-chain and
Asp153 on CD1d -chain. However, a single H-Bond would be
fromed with Asp153CD1d instead of two that could be observed by
the glyco-mimetic moieties (Figure 10).
4
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Figure 10. Docking results for MCS-0208 (13) with 3RTQ crystal, A)
Superposition of 10 poses obtained after iterative docking jobs B)
representative image of the best pose. CD1d carbons are coloured in green
while TCR α-chain carbons are coloured in pink. H-Bond interactions are
coloured in black dashed lines.
To reinforce this hypothesis, a short Molecular Dynamic (MD)
simulation was run to explore the system relaxation. The best
pose obtained for MCS-0208 (13) was selected as the starting
point to run 20 ns MD (300K, periodic boundary conditions, NPT
ensemble) in explicit water, using the Desmond software . Two
main parameters were analyzed from MD simulations: ternary
complex stability in terms of root-mean-square deviation
Figure 11. H-Bond monitoring of HS44 (3) (black dots) and compound 13
[
22]
(blue dots) during 20ns MD simulation .
As it could be expected, the number of interactions mediated by
head” group of new thioaryl-ceramide ligand MCS-0208 (13)
(
RMSD) and ligand’s H-Bond formation capacity all along
“
simulation. In this sense, interactions with key residues
Asp80CD1d, Thr156CD1d, Asp153CD1d, Asn30TCR, and Gly96TCR
were monitored. Ternary complex structure was mostly stable in
all cases with RMSD in the same range of reference HS44 (3).
H-Bond analysis showed conserved interactions with Asp80 and
Thr156 of CD1d in a similar frequency as HS44 (3), only one H-
Bond was observed with Asp153 versus the two observed with
HS44 (3) (Figure 11). This result was expected as our ligand
has a single hydroxyl group. Moreover, interactions with Gly96
on the TCR were lost for MCS-0208 (13) as well as for HS44 (3);
this result was rather unexpected as this interaction was in the
decreased due to low level of functionality compared to the
aminocyclitol scaffold. To further understand why this compound
seems to increase its potency when tested with human cells,
preliminary docking studies with human CD1d-TCR proteins
were done (Figure 12). The results point to a new  stacking
interaction of the phenyl ring of MCS-0208 and the unique
tryptophan 153 of human CD1d (which is a glycine in mice
protein). This interaction could increase the ArCer-CD1d
complex stability and therefore stabilizing the recognition by
TCR.
[
14]
crystal structure analysis of HS44 (3)
and was also observed
on our docking experiments. In a similar manner, in our previous
docking experiments MCS-0208 (13) formed this interaction, at
least intermittently. A correlation between H-Bond interaction
and the binding affinity together with the potency of NKT cells
activation is an attractive hypothesis which is beyond the scope
of this preliminary study.
[
23]
Figure 12. Docking results for MCS-0208 (13) with 4NE3
crystal. Two
different views are shown. CD1d carbons are coloured in green while TCR α-
chain carbons are coloured in pink. H-Bond interactions are coloured in yellow
dashed lines and  interactions are coloured in blue.
Overall, these results point to this compound as promising
candidate to be further study. More extensive structure-activity
studies could put some light on this new family potential and
deeper structural are needed to corroborate the above
mentioned structural hypothesis.
5
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Conclusions
Maenaka, K. Fukase, Y. Fujimoto, ACS Chem Biol 2016, 11, 3132–
3139.
[
[
[
10] J. Kishi, S. Inuki, E. Kashiwabara, T. Suzuki, N. Dohmae, Y. Fujimoto,
ACS Chem. Biol. 2020, 15, 353–359.
Here we have presented a new NKT cell recognized antigen,
MCS-0208 (13), with an unprecedented structure having an
ortho-hydroxymethyl substituted phenylthioether as a sugar
mimetic in the glycolipid. These results open the possibility of
further development for new families of compounds capable to
stimulate NKT cells. Considering the low functionalization of this
hit compound, we are optimistic of the potential of this new
family of NKT cell modulators with a more controllable activity
and selectivity. In summary, we have tested a small but
representative group of sphingolipid analogues as NKT cell
stimulators in vitro and the most potent antigens were tested in
vivo. Surprisingly, the aromatic compound MCS-0208 (13)
showed the highest stimulation capacity for both mice and
human NKt cells among all tested compounds. Although all of
them were weaker antigens than the reference GalCer, MCS-
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0208 (13) showed a better Th1 polarizing profile. Taking into
account that one of the drawbacks of GalCer (1) is the
overstimulation of NKT cells, the immmuno-stimulatory
properties showed by MCS-0208 (13) could be an interesting
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molecules as antigens for CD1d-restrictred NKT cell stimulation
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Acknowledgements
Financial support by the Ministry of Economy, Industry and
Competitiveness (CTQ2014-57020-R and CTQ2011-29549-
C02-01 grants) is gratefully acknowledged. Pre-doctoral FPU
Spanish research and teaching fellowship from the Ministry of
Education, Culture and Sport (FPU2013-01783 for R. Borràs-
Tudurí grant and AP200701826 for A. Alcaide grant) are also
acknowledged.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: NKT cells • alfa-galactosylcearmie • aryl-ceramide •
immunostimulation
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Entry for the Table of Contents
Breaking the rules of chemical structure of antigens for NKT cells stimulation, a single phenyl-hydorxymethyl moiety is able to
stimulate NKT cells via CD1d presentation. The replacement of alpha-galacose by hydroxymethyl-phenyl-thioether lead to a
interesting new NKT cell antigen, opening an unexplored chemical space for new antigens development with promising profile.
Institute and/or researcher Twitter usernames:
Institute: @IQAC_CSIC
Researcher: @roser_bt
7
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