Discovery of small-molecule inhibitors of the TLR1/TLR2 complex

Article abstract of DOI:10.1002/anie.201204910

An important regulator of innate immunity, the protein complex of Toll-like receptors 1 and 2 (TLR1/TLR2) provides an attractive target for the treatment of various immune disorders. The novel compound CU-CPT22 can compete with the binding of the specific lipoprotein ligand to TLR1/TLR2 (see picture) with high inhibitory activity and specificity. Repression of downstream signaling from TNF-α and IL-1β was also observed. Copyright

Full text of DOI:10.1002/anie.201204910

Angewandte
Chemie
DOI: 10.1002/anie.201204910
Drug Discovery
Discovery of Small-Molecule Inhibitors of the TLR1/TLR2 Complex**
Kui Cheng, Xiaohui Wang, Shuting Zhang, and Hang Yin*
Toll-like receptors (TLRs) are type I transmembrane proteins
that recognize pathogen-derived macromolecules and play
a key role in the innate immune system.[1–3] The pathogen-
derived macromolecules, which are broadly shared by patho-
gens but distinguishable from host molecules, are collectively
referred to as pathogen-associated molecular patterns
(PAMPs).[1,4] In humans, 10 TLRs respond to a variety of
PAMPs, including a lipopolysaccharide (TLR4), lipopeptides
(TLR2 associated with TLR1 or TLR6), bacterial flagellin
(TLR5), viral double-stranded (ds)RNA (TLR3), viral or
bacterial single-stranded (ss)RNA (TLRs 7 and 8), and
cytidine–phosphateguanosine (CpG)-rich unmethylated
DNA (TLR9), among others.[5–7]
TLR dimerization leads to the activation of nuclear
factor-kB (NF-kB) and interferon-regulatory factors (IRFs),
and these transcription factors in turn induce the production
of pro-inflammatory cytokines and type I interferons (IFNs),
respectively.[1,8] Finally, the key outputs from TLR activation
are inflammatory cytokines such as tumor necrosis factor
(TNF) and interleukin 1b (IL-1b), which have proven to be
directly relevant to inflammatory diseases.[9] TLR2, signaling
as a heterodimer with either TLR1 or TLR6, recognizes
a wide range of ligands, many of which are from Gram-
positive bacteria.[10] The molecular recognition by TLR2 was
largely explained when the crystal structure of the TLR1/
TLR2 heterodimer in complex with its specific lipoprotein
ligand, Pam3CSK4, was solved.[11] In this structure (Figure S1a
in the Supporting Information), the extracellular domains of
TLR1 and TLR2 form an M-shaped heterodimer, with the
two N termini extending outward in opposite directions. The
lipid chains of Pam3CSK4 bridge the two TLRs, contributing
to the formation of the heterodimer. Two of the three lipid
chains of Pam3CSK4 interact with a hydrophobic pocket in
TLR2, and the amide-bound lipid chain lies in a hydrophobic
channel within TLR1. The ligand-bound complex of TLR1
and TLR2 is stabilized by protein–protein contacts near the
ligand-binding pocket.[9,11]
(HSV-1) is regulated by TLR1/TLR2.[12,13] TLR1/TLR2
antagonists have been suggested to have beneficial effects in
both chronic and acute inflammatory diseases ranging from
acne[12] to sepsis,[13] and can also attenuate pulmonary
metastases of tumors.[14] However, a significant bottleneck
in the field can be attributed to the lack of efficient and
specific probes for the TLR1/TLR2 signaling pathway. Even
though the limited success of TLR2 regulators has been
reported in literature,[15] low-molecular-weight inhibitors with
high potency and specificity against TLR1/TLR2 have not
been reported to our knowledge.
Novel inhibitors of TLR1/TLR2 were obtained by cell-
based screening of the small-molecule library NCI-2 Diversity
consisting of 1363 compounds. Screening was performed in
a 96well plates format using our previously established high-
throughput nitric oxide (NO) assay in RAW264.7 macro-
phage cells (details on the screening method are given in
Figure S2 in the Supporting Information).[16,17] Synthetic
triacylated lipoprotein Pam3CSK4 was employed to selec-
tively activate TLR1/TLR2 signaling, resulting in the expres-
sion of inducible nitric oxide synthase (iNOS) and the
production of NO in RAW264.7 macrophage cells.[16] We
monitored the NO level as an indicator of Pam3CSK4-induced
TLR1/TLR2 activation to determine the potency of the
inhibitors.
We identified nine initial hits (Scheme S1 in the Support-
ing Information) that inhibited TLR1/TLR2 activation by at
least 70% at 3.0 mm with no significant cytotoxicity (Figure S3
in the Supporting Information). The most potent compound
was NCI35676 (Table 1, a natural product named purpuro-
gallin obtained from nutgalls and oak bark) with an IC50 of
(2.45 Æ 0.25) mm (Figure S4 in the Supporting Information).
NCI35676 has been reported to display antioxidant[18] and
anticancer[19,20] properties, and it also modulates inflamma-
tory response activity.[21] Nonetheless, work on the molecular
target of purpurogallin and its derivatives has not yet been
reported. Further, when we evaluated TLR specificity we
found that of the nine initial hits, only NCI35676 specifically
inhibited TLR1/TLR2 signaling but not that of other homol-
ogous TLRs (Figure S5 in the Supporting Information).
Based on the promising preliminary results, we attempted
to optimize the structure of NCI35676 to improve its
inhibitory potency and selectivity. We designed a series of
NCI35676 analogues to explore the structure–activity rela-
tionship (SAR) around the benzotropolone core scaffold. A
one-pot synthesis with sequential additions of a) phosphate–
citrate buffer (pH 5), b) horseradish peroxidase enzyme,
c) 3% H2O2 produced the bicyclic scaffold (Scheme 1 and
Scheme S2 in the Supporting Information).[22] This method
provides a concise, general synthetic route that can afford the
benzotropolone derivatives with an overall yield of 15–60%.
Compound 2 was selected as a representative for further
Previous reports have demonstrated that the cytokine
response to human cytomegalovirus (CMV), lymphocytic
choriomeningitis virus (LCMV), and herpes simplex virus1
[*] Dr. K. Cheng, Dr. X. H. Wang, S. T. Zhang, Prof. Dr. H. Yin
Department of Chemistry and Biochemistry
and the BioFrontiers Institute
University of Colorado at Boulder, Boulder, CO 80309 (USA)
E-mail: hubert.yin@colorado.edu
[**] We thank the U.S. National Institutes of Health (DA026950,
DA025740s and NS067425) for financial support of this work. The
sTLR2 DNA plasmid was kindly provided by Dr. Chiaki Nishitani and
Dr. Yoshio Kuroki.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204910.
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carbon aliphatic chain at the R6 position, which likely allows
for hydrophobic contacts to the surface residues of the TLR1/
TLR2 complex (Figure 1b).
Table 1: Analysis of the structure–activity relationship of the benzotro-
polone analogues for the inhibition of NO production in RAW264.7 cells.
The SAR for this series indicated that the total number of
hydroxy groups was critical. Methylation of one hydroxy
group at the R1 position (4) had a modest effect on its activity,
while methylation of all four hydroxy groups (6) resulted in
significant decrease of inhibition (Table 1). Introduction of
a fluorine substituent at the R1 position (3) decreased the
activity about 20-fold, suggesting that an electron-withdraw-
ing group is not favorable here. We also found that the seven-
membered-ring configuration in the benzotropolone scaffold
plays an important role for inhibitory activity as determined
by the Diels–Alder [4+2]-cycloaddition products (6 versus 25,
9 versus 26).
Compound R1
R3
R4
R5
IC50 [mM][a]
NCI35676
OH
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
2.45Æ0.25
3.13Æ0.11
2.25Æ0.31
22.7Æ1.4
1
2
3
4
5
6
7
8
9
H
H
F
OCH3
OCH3
OCH3
OCOCH3
H
H
4.83Æ0.25
11.7Æ1.1
CH3
CH3
H
CH3
CH3
H
39.9Æ0.9
4.83Æ0.25
1.42Æ0.21
2.35Æ0.41
We found that conversion of the hydroxy group at R1 to
a methoxy group eliminated the formation of by-products, but
still retained the activity of NCI35676 (Scheme S2 in the
Supporting Information). Therefore, in the following SAR
studies, the methoxy group was fixed at the R1 position.
Meanwhile, the seven-membered ring in the benzotropolone
scaffold was kept and substituent groups were introduced at
the R6 position. The addition of a carboxyl group at the R6
position decreased the activity by approximately fivefold (4
versus 10), while esterification of this carboxyl group (11)
returned the activity to the NCI35676 level, indicating that R6
may be critical for the inhibitory activity.
OCOCH3 COCH3
COCH3
OCOCH3 COCH3 COCH3 COCH3
R1
R6
COOH
COOCH3
COOH
10
11
12
OCH3
OCH3
H
21.5Æ0.4
3.11Æ0.75
16.5Æ0.8
13
H
COOCH3
9.01Æ0.50
2.83Æ0.44
2.47Æ0.71
2.83Æ0.44
0.72Æ0.14
1.01Æ0.10
3.24Æ0.13
1.26Æ0.31
1.36Æ0.21
0.58Æ0.09
4.11Æ0.74
1.36Æ0.21
14
15
16
17
18
19
20
21
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
COOCH2CH3
COOCH(CH3)2
COO(CH2)3CH3
COO(CH2)7CH3
COO(CH2)9CH3
COO(CH2)13CH3
CONH(CH2)3CH3
CONH(CH2)5CH3
COO(CH2)5CH3
CH2OH
By introducing various aliphatic chains at the R6 position,
we found that CU-CPT22 with a six-carbon chain displayed
the highest inhibitory activity for TLR1/TLR2 (Table 1). This
increased potency was likely caused by a good fit of the six-
carbon chain into the substrate tunnel of the TLR1 hydro-
phobic region (Figure 1b). When we replaced the ester with
the amide group at the R6 position in CU-CPT22, the activity
slightly decreased (21). Reducing the carboxyl group to
a -CH2OH group (23) or introducing a large substitute at the
R6 position (24) led to no significant change in activity. In
summary, we identified compound CU-CPT22 as the lead
structure, which shows dose-dependent inhibitory effects in
blocking Pam3CSK4-induced TLR1/TLR2 activation with an
IC50 of (0.58 Æ 0.09) mm (Figure 1a).
CU-CPT22
23
24
CONH(o-tolyl)
25
26
74.6Æ2.9
14.8Æ0.5
[a] IC50 values and corresponding standard deviations were determined
from at least three independent repeats.
Biophysical tests were carried out for CU-CPT22, along
with the negative control compound 6, to demonstrate that
CU-CPT22 directly binds to TLR1/TLR2. The TLR2 protein
was expressed in the baculovirus insect cell expression system
using the methods described by Kuroki and co-workers.[24]
The activities of the TLR2 and TLR1 protein were validated
by the fluorescence anisotropy assay with the rhodamine-
labeled, synthetic triacylated lipoprotein Pam3CSK4 as the
probe (Figure 2a). It was demonstrated that CU-CPT22 was
able to compete with Pam3CSK4 for binding to TLR1/TLR2
with an inhibition constant (Ki) of (0.41 Æ 0.07) mm, which is
consistent with its potency observed in the whole-cell assay.
The anisotropy of rhodamine-labeled Pam3CSK4 showed
a robust increase from 0.168 to 0.275 (Figure 2a) upon
addition of TLR1/TLR2 (excitation = 549 nm; emission =
566 nm). This increase is consistent with the anisotropy
changes seen with ligand–receptor pairs of comparable
sizes.[25] Increasing the concentration of CU-CPT22 to 6 mm
Scheme 1. One-pot synthesis of CU-CPT22: a) phosphate–citrate buffer
(pH 5), 0.2m Na2HPO4/0.1m citrate (1:1); b) horseradish peroxidase;
c) four aliquots of 3% H2O2, 42% overall yield.
NMR characterizations (1H/13C, HSQC, HMBC, and COSY
included in Figure S6 in the Supporting Information).
Further screening of 26 structural analogues yielded
additional hits, the most potent being CU-CPT22, which
showed an IC50 of (0.58 Æ 0.09) mm (Figure 1a). The improved
IC50 of CU-CPT22 appears to be due to the addition of a six-
2
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Figure 1. a) Dose-dependent inhibition of NO production in RAW264.7 macrophage cells by CU-CPT22 and the negative control compound 6.
b) Binding site of CU-CPT22 (shown in the stick representation) in TLR1/TLR2 predicted by the program Glide 5.6.[23] The six-carbon chain fits well
into the hydrophobic channel of hTLR1 and has key hydrophobic interactions with Val311, Phe312, Pro315, and Val339.
ing a ligand-binding domain with a double-horseshoe shape.[7]
We therefore tested CU-CPT22 against a panel of homolo-
gous TLRs, including TLR1/TLR2, TLR2/TLR6, TLR3,
TLR4, and TLR7 using TLR-specific ligands to selectively
activate a particular TLR-mediated NO production. We
found that CU-CPT22 inhibits TLR1/TLR2 signaling without
affecting other TLRs, showing that it is highly selective in
intact cells (Figure 3).
Importantly, CU-CPT22 was found to have no significant
cytotoxicity at various concentrations up to 100 mm in
RAW264.7 cells using the established MTT methodology
(Figure S7 in the Supporting Information). Furthermore,
kinase profiling showed that compound CU-CPT22 demon-
strated minimal nonspecific inhibition against a panel of 10
representative kinases (PDGFRB, MET, DDR2, SRC,
MAPK1, PAK1, AKT1, PKC-g, CAMK1, and PLK4) (Fig-
ure S8 in the Supporting Information). Lastly, we used
a secondary cellular assay to confirm that CU-CPT22 also
inhibits the downstream signaling transduction. In addition to
the suppression of NO production, we also investigated the
release of the proinflammatory cytokines TNF-a and IL-1b,
Figure 2. Fluorescence anisotropy titration: a) titration of the TLR1/
which are also regulated by the TLR1/TLR2 signaling
TLR2 protein into the rhodamine-labeled Pam3CSK4 results in a signifi-
cant increase of fluoresence anistropy. Added CU-CPT22 competes
with Pam3CSK4 and results in lower fluoresence anisotropy; this
demonstrates competitive binding between CU-CPT22 and Pam3CSK4
for TLR1/TLR2. Data were fitted using a one-site competition model
(R2 >0.98). b) Normalized binding of CU-CPT22 compared with the
negative control, compound 6.
decreased the anisotropy to background levels, presumably
because of the release of the fluorescently labeled Pam3CSK4
probe. This data was then fit to a one-site competition model.
From the good fit (R2 > 0.98) we infer that CU-CPT22 and
Pam3CSK4 compete for the same binding site on the surface of
the TLR1/TLR2 heterodimer. By contrast, compound 6,
which was used as a negative control in the anisotropy assay,
demonstrated negligible binding up to 6 mm (Figure 2b).
These results further support the premise that CU-CPT22 can
compete with Pam3CSK4 binding to TLR1/TLR2.
Figure 3. Specificity test for CU-CPT22 (0.5 mm) with with TLR-specific
agonists used to selectively activate the respective TLRs: 1. TLR3:
15 mgmLÀ1 polyinosinic–polycytidylic acid (PIC), 2. TLR4: 10 ngmLÀ1
lipopolysaccharide (LPS), 3. TLR1/TLR2: 200 ngmLÀ1 Pam3CSK4,
4. TLR2/TLR6: 10 ngmLÀ1 (S,R)-(2,3-bispalmitoyloxypropyl)-Cys-Gly-
Asp-Pro-Lys-His-Pro-Lys-Ser-Phe (FSL-1), and 5. TLR7: 100 nm 4-amino-
2-(ethoxymethyl)-a (R848) were used to selectively activate respective
TLRs.
One challenge in developing inhibitors to target TLRs is
to engineer specificity and potency. There are at least 13
homologous TLRs present in murine macrophages, all shar-
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Received: June 22, 2012
Published online: && &&, &&&&
Keywords: drug discovery · inhibitors · innate immunity ·
.
Toll-like receptors
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Figure 4. Inhibition of downstream signaling. ELISA assay results
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cascade. We found that CU-CPT22 can inhibit about 60% of
TNF-a (Figure 4a) and 95% of IL-1b (Figure 4b) at 8 mm.
These results further indicate that compound CU-CPT22
suppresses
response.
the
TLR1/TLR2-mediated
inflammation
It is worth noting that CU-CPT22 can inhibit TLR1/
TLR2, while no significant inhibition to TLR2/TLR6 is
observed (Figure 3). Based on these experimental observa-
tions, we attempted to obtain insights into the possible
binding modes of CU-CPT22 (Figure 1b). In the absence of
an X-ray crystal structure (structural analysis of the TLR/
ligand complexes is highly challenging due to the difficult
protein preparation), we carried out computational modeling
to illustrate the potential binding mode of CU-CPT22 with
TLR1/TLR2. Comparing the crystal structures of TLR1/
[11]
TLR2/Pam3CSK4 (Figure S1a in the Supporting Informa-
[26]
tion) and TLR2/TLR6/Pam2CSK4
(Figure S1b), we
observed that two lipid chains of Pam3CSK4 and Pam2CSK4
(Figure S1a and S1b, yellow) interact with a hydrophobic
channel in TLR2, and the amide-bound lipid chain of
Pam3CSK4 (Figure S1a, red) lies in a second hydrophobic
channel of TLR1 that does not exist between Pam2CSK4 and
TLR6 in the TLR2/TLR6/Pam2CSK4 complex.[11,25] The
remarkable selectivity for TLR1/TLR2 is likely due to the
specific contacts between the aliphatic chain at the R6
position of CU-CPT22 and the hydrophobic channel of
TLR1 (Figure 1b), as this hydrophobic channel is absent in
TLR6[26] (Figure S1b).
In conclusion, we have identified a novel small molecule,
CU-CPT22, that can compete with the synthetic triacylated
lipoprotein (Pam3CSK4) in binding to TLR1/TLR2 with
potency and specificity. The downstream-signaling experi-
ments further indicated that CU-CPT22 suppresses the
TLR1/TLR2-mediated inflammation response. This novel,
small-molecule agent provides a much needed molecular
probe for studying ligand interactions of the TLR1/TLR2
protein complex.
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Chemie
Communications
Drug Discovery
An important regulator of innate
immunity, the protein complex of Toll-like
receptors 1 and 2 (TLR1/TLR2) provides
an attractive target for the treatment of
various immune disorders. The novel
compound CU-CPT22 can compete with
the binding of the specific lipoprotein
ligand to TLR1/TLR2 (see picture) with
high inhibitory activity and specificity.
Repression of downstream signaling
from TNF-a and IL-1b was also observed.
K. Cheng, X. H. Wang, S. T. Zhang,
H. Yin*
&&&& — &&&&
Discovery of Small-Molecule Inhibitors of
the TLR1/TLR2 Complex
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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