Inhibition of HIV-1 capsid assembly: Optimization of the antiviral potency by site selective modifications at N1, C2 and C16 of a 5-(5-furan-2-yl-pyrazol- 1-yl)-1H-benzimidazole scaffold

Article abstract of DOI:10.1016/j.bmcl.2012.10.034

A uHTS campaign led to the discovery of a 5-(5-furan-2-ylpyrazol-1-yl)-1H- benzimidazole series that inhibits assembly of HIV-1 capsid. Synthetic manipulations at N1, C2 and C16 positions improved the antiviral potency by a. The X-ray structure of 33 complexed with the capsid N-terminal domain allowed identification of major interactions between the inhibitor and the protein.

Full text of DOI:10.1016/j.bmcl.2012.10.034

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7512–7517
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Inhibition of HIV-1 capsid assembly: Optimization of the antiviral potency
by site selective modifications at N1, C2 and C16
of a 5-(5-furan-2-yl-pyrazol-1-yl)-1H-benzimidazole scaffold
Martin Tremblay a, , Pierre Bonneau a, Yves Bousquet a, Patrick DeRoy a, Jianmin Duan a,
⇑
Martin Duplessis a, Alexandre Gagnon b, , Michel Garneau a, Nathalie Goudreau a, Ingrid Guse a,
Oliver Hucke a, Stephen H. Kawai a,§, Christopher T. Lemke a, Stephen W. Mason c,à, Bruno Simoneau a,
Simon Surprenant a, Steve Titolo a, Christiane Yoakim a
a Boehringer Ingelheim (Canada) Ltd, Research & Development, Laval, Québec, Canada H7S 2G5
b Université du Québec à Montréal, Département de Chimie, C.P. 8888, Succ. Centre-Ville, Montréal, Québec, Canada H3C 3P8
c Bristol-Myers Squibb, Virology, 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A uHTS campaign led to the discovery of a 5-(5-furan-2-ylpyrazol-1-yl)-1H-benzimidazole series that
inhibits assembly of HIV-1 capsid. Synthetic manipulations at N1, C2 and C16 positions improved the
antiviral potency by a factor of 1000. The X-ray structure of 33 complexed with the capsid N-terminal
domain allowed identification of major interactions between the inhibitor and the protein.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 August 2012
Revised 2 October 2012
Accepted 8 October 2012
Available online 16 October 2012
Keywords:
HIV-1
Capsid assembly inhibitor
Benzimidazole
X-ray crystal structure
The United Nations World Health Organization estimated that
in 2009 the population infected by HIV had reached 33 million
individuals with 2 million AIDS-related deaths per year.1 Since
the discovery of the virus in 1981, more than 26 FDA-approved
drugs have been added to the antiretroviral arsenal against HIV.
The current standard of care is a multi-drug therapeutic regime, of-
ten referred to as highly active antiretroviral therapy (HAART). The
development of HAART has considerably improved the life expec-
tancy of HIV positive patients over the past 25 years.2 Although,
the HAART regime can efficiently inhibit viral replication for many
years, drug resistance still occurs, resulting in a continuing need for
the development of novel HIV inhibitors. In addition to inhibiting
new targets within the HIV replication cycle, these compounds
must also deliver safe toxicological profiles and be compatible with
long-term treatment.3
The HIV-1 capsid protein (CA), which plays an essential role in
both the early and late phases of the HIV life cycle, is a promising
novel antiviral target.4 During viral maturation, proteolytic cleav-
age of the 55-kDa Gag polyprotein releases CA, which reassembles
to form a cone shaped structure that encloses the viral RNA gen-
ome and all the enzymatic activities required for future rounds
of infection. The proper assembly of CA is essential for HIV infectiv-
ity since CA mutations that prevent core assembly result in non-
infectious viral particles.5 CA is comprised of two independently
folding domains, an N-terminal domain (CANTD) and a C-terminal
domain (CACTD), which are separated by a short flexible linker.
CANTD self-associates into hexameric rings which are further rein-
forced by intermolecular CANTD–CACTD interactions. In addition,
intermolecular CANTD–CACTD interactions made between adjacent
CA proteins of a hexamer reinforce the basic hexamer unit. Finally
homodimeric CACTD–CACTD interactions allow each hexamer to
interact with six neighboring hexamers, thereby perpetuating the
hexagonal lattice.6 Pioneering work by Sundquist and coworkers7
led to the discovery that CA can assemble into cone-like particle
in vitro, which allowed for the identification by us8a,b and oth-
ers8c–k of small molecule CA inhibitors.
⇑
Corresponding author. Tel.: +1 450 682 4640; fax: +1 450 682 4189.
E-mail address: martin.tremblay@boehringer-ingelheim.com (M. Tremblay).
Present address.
Present address.
à
§
Current address: Department of Chemistry and Biochemistry, Concordia Univer-
Screening of our corporate compound collection with our capsid
sity, 7141 Sherbrooke Street W., Montreal, Quebec, Canada H4B 1R6. Tel.: +1 514 848
2424x3331.
assembly assay (CAA)8a let to the identification of benzimidazole 1
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.034

M. Tremblay et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7512–7517
7513
N
N
1
O
N
N
NH
SAR
N
O
N
N
NH2
NH2
N
5
O
3
O
10
13
1
2
16
IC50 (CDA): 6.0 µM
EC50: 28 µM
CC50: 54 µM
IC50 (CDA): 1.0 µM
EC50: 3.5 µM
CC50: 17 µM
Scheme 1.
(Scheme 1).9 With an assay wall10 of approximately 200–400 nM,
the resolution of CAA was not enough for this series optimization.
Consequently, the capsid disassembly assay (CDA)11 has been
developed to follow our structure-activity relationship. This new
assay improved by a factor of 10 the assay wall and was used dur-
ing the program. Benzimidazole 1 showed a modest IC50 (CDA) va-
give the corresponding diketone 4 (Scheme 2). Diketone 7 was
synthesized using trifluoromethylfuran derivative 5. Oxidation of
the alcohol 5 to the corresponding acid, followed by treatment
with oxalyl chloride, led to acyl chloride 6. Alkylation of the
anion of tert-butyl propionoacetate with 6 followed by acidic
decarboxylation gave the desired diketone 7. The 2-aminopyridine
8 was converted to the 2-methoxypyridine 9 via the formation of
the corresponding pyridone followed by regioselective O-methyla-
tion. Coupling of 5-bromopyridine 9 in the presence of CuCN
followed by hydrogenation led to desired pyridinemethylamine
10. Temporary protection of the primary amine of 10 as
lue of
6 lM, but no detectable antiviral activity (CC50/EC50
ꢀtwofold).12 We began hit-to-lead efforts to address the optimiz-
ability of the scaffold, improve potency in the CDA and identify
compounds with clear antiviral potency. We rapidly realized that
substitution on the furylpyrazole moiety was limited to an ethyl
at C10. On the other hand, N1 and C2 positions of the benzimid-
azole scaffold were found to be very permissive, which we hoped
would help improve the potency of the series. Replacing substitu-
ent at C2 with a 4-benzamide group and having a cyclopropylm-
ethyl group at N1 led to the identification of compound 2, which
a
tert-butyloxycarbonyl derivative, followed by simultaneous
methylation/deprotection gave pyridonemethylamine 11.
The preparation of inhibitors started with diazotization of 12
followed by tin reduction to give the corresponding hydrazine 13
(Scheme 3). Acidic condensation with diketone 4 and 7 led to pyr-
azoles 14 and 15, respectively, with complete regioselectivity. Sim-
ple aromatic nucleophilic substitution with different amines
followed by reduction of the nitro group using Sn/HCl gave dia-
mines 16–19. The benzimidazole ring system was easily obtained
using a condensation/oxidation methodology developed in our
laboratories.14 Consequently, the obtained diamines 16–19 were
exhibited an IC50 value of 1.0
activity with an EC50 value of 3.5
l
M and possesses clear antiviral
lM (CC50 = 17
l
M).13 This com-
munication describes the antiviral potency optimization by site
selective modification at positions N1, C2 and C16.
Synthesis of the building blocks started with the alkylation of
the anion of 2-acetyl-5-methylfuran 3 with propanoyl chloride to
O
O
O
a
O
O
3
4
O
O
O
b, c
O
d, e
O
Cl
O
HO
CF3
CF3
Br
CF3
6
7
5
Br
f, g
h, i
NH2
MeO
N
MeO
N
H2N
N
8
9
10
j, k
NH2
O
N
11
Scheme 2. (a) LDA, propanoyl chloride, THF, ꢁ78 °C then RT, 90%; (b) Dess–Martin periodinane, CH2Cl2, then NaClO2, 2-methyl-2-butene, t-BuOH, phosphate buffer pH 7,
quant.; (c) oxalyl chloride, CH2Cl2, cat. DMF, 0 °C, 99%; (d) tert-butyl propionoacetate, Et3N, MgCl2, MeCN; (e) TFA, CH2Cl2, 60% (2 steps); (f) NaNO2, H2SO4, H2O, 0 °C to RT,
67%; (g) MeI, Ag2CO3, CH2Cl2, quant.; (h) CuCN, DMF, 130 °C, 81%; (i) H2, Pd/C 10%, aq. HCl, MeOH, quant.; (j) (Boc)2O, Et3N, CH2Cl2, 87%; (k) MeI, CH2Cl2, sealed tube 120 °C,
48 h, quant.

7514
M. Tremblay et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7512–7517
F
F
c, d
b
N
N
NO2
R1
14
O
O
O
X
NO2
O
R1
12 X= NH2
13 X= NHNH2
14 R1= Me
15 R1= CF3
4 or 7
a
R2
NH
R2
N
O
e
N
N
NH2
N
NH2
N
N
O
O
OMe
OMe
OH
N
OH
N
18
17
20
16
21
23
2
R2=
OMe
N
OMe
N
O
f, g
NH
19
22
Scheme 3. (a) NaNO2, HCl, SnCl2, ꢁ25 °C to RT, 55%; (b) diketone 4 or 7, AcOH, 70–80%; (c) R2–NH2, Et3N, THF, 70–98%; (d) Sn, aq. HCl, THF, quant.; (e) 4-formyl-benzamide,
oxone, DMF, H2O, 6–61%; (f) 33% HBr/AcOH, 100 °C; (g) NH3/dioxane, TBTU, Et3N, DMF, 6%.
cyclized using 4-formylbenzamide with OxoneÒ as the oxidant to
give 2 and 20–22, respectively. Deprotection of the methoxypyri-
dine 22 was accomplished by using 33% HBr in AcOH, which also
cleaved the amide to the acid. Consequently, simple amide cou-
pling using ammonia in dioxane and TBTU led to 23.
A series of 2-hydroxybenzaldehydes were condensed with dia-
mine 18 to yield benzimidazoles 24–26 (Scheme 4). Acid 26 was
coupled with dimethylamine using TBTU to give amide 27. Simi-
larly diamine 19 was converted to benzimidazoles 28–30. Depro-
tection of the methoxypyridines to the pyridones was achieved
upon treatment with HBr in AcOH to give 31–33, respectively. Fi-
nally, acid 33 was also converted into the corresponding dimeth-
ylamide 34 as described above.
Intermediates 35–37 were obtained from SNAr substitution by
different amines on trifluoromethylfuran analogue 15 followed
by reduction and condensation with 3-formyl-4-hydroxybenzoic
acid as described above. The methoxypyridines 35 and 36 were
converted to the corresponding pyridones using HBr in AcOH and
amide coupling led to inhibitors 38–41. (Scheme 5)
We rapidly found that introduction of substituted aryls and
3-pyridines were well tolerated at the N1 position (Table 1).
Replacement of the cyclopropylmethyl group in 2 by a 3-pyridi-
nemethyl substituent (inhibitor 20) resulted in a threefold gain
in potency in the CDA. The 2-methoxyphenol and methoxypyridine
derivatives 21 and 22 exhibited similar IC50 values but 21 was
found to be significantly more potent in the antiviral assay with
found crucial to improve the antiviral activity when different aryls
are introduced at C2.
Keeping the N1 2-methoxyphenol side chain that produced the
most potent inhibitor (21) in the antiviral assay, we investigated
the C2 position (Table 1). Replacement of the 4-benzamide moiety
in 21 with a 2-hydroxyphenyl substituent led to 24, which was
found to be twofold more potent in the CDA. Reintroducing elec-
tron-withdrawing groups on the 2-hydroxyphenol moiety was
found to be beneficial for potency. Incorporating a fluorine atom
at the 5 position (25) gave a slight gain in intrinsic potency in
comparison with 24. Adding an acid (26) or an amide group
(27) at this position resulted in substantial gain in potency in
the CDA. On the other hand, antiviral potency could not be
improved further with these 2-methoxyphenol N1 side chains.
In contrast with the pyridone analog 23, introduction of these
2-hydroxyphenyl groups at C2 had a positive impact on both
intrinsic and antiviral potencies. Inhibitors 31, 32 and 34 exhib-
ited a 20- to 50-fold gain in the antiviral assay compared with
23. These analogues were at the limit of the resolution of the
CDA, necessitating development of a more sensitive assay. A
fluorescence polarization (FP)15 displacement assay was therefore
developed, with a fluorescein linked onto the carboxylate of 33.
With a Kd of 0.088
lM, this competition assay improved the assay
wall to approximately 0.014
l
M.
The X-ray structure of 33 complexed with CANTD confirmed CA
as the target of the series and revealed the intermolecular interac-
tions leading to compound binding.16 The inhibitor induces the for-
mation of a pocket at the base of CANTD (Fig. 1). The structural
movements and functional effects accompanying the formation
of this pocket are described elsewhere.8a The furylpyrazole moiety
is buried most deeply in the pocket, thus explaining the observed
an EC50 value of 0.64
most potent inhibitor in the CDA with an IC50 value of 0.17
Surprisingly, this modification led to a significant loss in antiviral
potency (EC50 = 13 M). Although poor potency in our cell-based
assay was measured, substituted pyridone side chain was later
lM. The pyridone derivative 23 gave the
l
M.
l

M. Tremblay et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7512–7517
7515
OH
MeO
R3
OHC
HO
R3= H, F, CO2H
N
N
a
N
R3
N
18
HO
c
O
24 R3= H
25 R3= F
26 R3= CO2H
27 R3= CONMe2
a
19
H
N
O
MeO
N
R3
R3
N
N
N
b
N
N
N
N
N
HO
c
HO
O
O
31 R3= H
32 R3= F
28 R3= H
29 R3= F
33 R3= CO2H
34 R3= CONMe2
30 R3= CO2H
Scheme 4. (a) Oxone, DMF, H2O, 8–72%; (b) 33% HBr/AcOH, 100 °C, 17–45%; (c) Me2NH, TBTU, Et3N, THF, 14–25%.
R2
N
CO2H
a, b, c
d, e
15
N
N
N
HO
O
CF3
O
N
OMe
N
OMe
N
R2=
36
37
35
O
N
O
O
NH
NH
O
R2=
R2
N
R4
N
N
N
R4=
R4=
R4=
N
HO
O
N
CF3
N
NMe2
38
39
41
40
Scheme 5. (a) R2–NH2, Et3N, THF, 70–98%; (b) Sn, aq. HCl, THF, quant.; (c) 3-formyl-4-hydroxybenzoic acid, Oxone, DMF, H2O, 90–98%; (d) 33% HBr/AcOH, 100 °C, quant. (only
for 35 and 36); (e) dimethylamine or pyrrolidine TBTU, Et3N, THF, 26–60%.
sensitivity of this region to modification. Interactions within
the pocket are largely hydrophobic, with the exception of a key
hydrogen bond between the pyrazole and the backbone NH of dis-
placed residue Phe-32. The benzimidazole moiety stacks between

7516
M. Tremblay et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7512–7517
Table 1
microsomes (45 and 30 min, respectively) and a poor Caco-2 per-
meability of 0.19 ꢂ 10ꢁ6 cm/s. N-methylation of the pyridone re-
sulted in an additional twofold gain in antiviral potency for
inhibitor 40. Similar potency was observed with the introduction
of another methyl group on the pyridone at position 6 (analogue
41). These modifications also had a beneficial impact on the
Caco-2 permeability, with increases to 6.8 and 7.2 ꢂ 10ꢁ6 cm/s
for compound 40 and 41, respectively. Unfortunately, microsome
stability was reduced by these substitutions. In these cases, meta-
bolic stability upon incubation with rat and human liver micro-
somes were 25 and 11 min. for 40 and 18 and 10 min. for 41,
respectively.
In conclusion, we have demonstrated that the inhibition of HIV
capsid assembly is a valid approach to inhibit HIV replication. We
have optimized a hit compound with no measurable antiviral
activity to an advanced lead compound with an EC50 value of
27 nM, which is the most potent HIV capsid assembly inhibitor re-
ported to date. The synthetic approach allowed diversification at
N1 and C2 positions. We discovered that introduction of a pyridone
side chain at N1, a 2-hydroxyphenyl appendage at C2 and a C16 tri-
fluoromethyl group were crucial for improving the antiviral po-
tency. The crystal structure of 33 complexed with CANTD
identified interactions between the inhibitor and the protein that
were consistent with the observed SAR. Though promising, this
series was unfortunately stopped because of poor metabolic stabil-
ity, pharmacokinetic profile and limited SAR opportunities to ad-
dress these liabilities.
Activities and cytotoxicity of substituted benzimidazole derivatives
Compound
IC50 CDA (
l
M)
IC50 FP (
l
M)
EC50
28
3.5
2.6
0.64
3.5
13
6.4
10
(
l
M)
CC50 (lM)
1
2
6.0
1.0
—
—
—
—
—
—
—
—
0.55
—
0.69
—
0.65
0.044
0.059
0.061
0.038
0.067
54
17
19
12
13
>39
>22
>21
>46
16
>26
>16
>46
>23
>23
20
20
21
22
23
24
25
26
27
31
32
33
34
38
39
40
41
0.36
0.79
0.83
0.17
0.41
0.28
0.088
0.12
0.055
0.041
0.056
0.049
—
6.1
0.63
0.26
0.26
>46
0.59
0.091
0.062
0.028
0.027
—
—
—
18
21
the aromatic sidechains of Phe-32 and His-62, orienting N1 and C2
substituents toward solvent, and positioning N3 for a water-
mediated hydrogen bond with the backbone NH of Ala-65. The
N1 pyridone lies along the surface of the protein, contacting the
side-chains of Ala-31 and Phe-32. The N2 benzoic acid moiety
protrudes directly into solvent, with the phenolic oxygen reaching
back to form a hydrogen bond with His-62. It is important to note
that portions of the inhibitor that are observed as solvent exposed
when bound to CANTD may well form important protein interac-
tions in the context of full length, assembled CA.
Acknowledgments
The authors would like to acknowledge Jean-François Mercier
and Elizabeth Wardrop for IC50 and EC50 value determinations,
respectively, and Normand Aubry, Colette Boucher, Michael Little
and Serge Valois for analytical support. We are also grateful to
Michael Bös, Richard Bethell and Michael Cordingley for leadership
and guidance in chemistry and biology. Finally, we extend our
gratitude to Professor Wesley Sundquist for helpful discussions
at the early stage of this project.
Using inhibitor 34 as starting point, the C16 position was revis-
ited and it was found that replacing the methyl substituent by a
trifluoromethyl group (cf. 34 and 38 in Table 1) gave a sixfold gain
in antiviral potency although there was little impact on the IC50
values. Further modification of the amide group led to the identifi-
cation of pyrrolidine amide derivative 39 which exhibited IC50 and
EC50 values of 61 and 62 nM, respectively. This analogue showed
poor metabolic stability upon incubation with rat and human liver
Figure 1. Binding of 33 to CANTD. (A) Location and surface representation of the binding pocket on CANTD. CANTD is illustrated in ribbon-form and 33 is shown as sticks.
Lipophilic, neutral and hydrophilic surfaces are colored green, white and pink, respectively. (B) Details of 33 binding. Representations are similar to A, with the addition of
interacting residues in lineform, hydrogen bonds as green lines, an ordered water molecule as a red sphere and some residues in the foreground were removed for clarity.

M. Tremblay et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7512–7517
7517
10. The assay wall corresponds to the minimal measured IC50 value and usually
can be approximated by half target protein concentration.
References and notes
11. Reacti-Bind Neutravidin Coated Black 384-Well plates (Pierce Cat# 15402)
1. UNAIDS/WHO ‘‘AIDS Epidemic Update 2009’’, November 2009, Geneva. http://
data.unaids.org/pub/Report/2009/JC1700_Epi_Update_2009_en.pdf (accessed
May 2012).
were first washed with 80
NaCl; 10 ZnSO4; 0.0025% CHAPS (w/v); 50
Immobilization of a 50-end biotin labeled (TG)25 oligonucleotide (Integrated
DNA Technology Inc.) was then carried out by adding 50 l/well of a 25 nM
solution of oligonucleotide in Buffer A + 5 mg/ml BSA and incubating
overnight. Unbound material was removed by two 80 l/well washes with
Buffer A. Assembly reactions were performed in 60 l/well reactions
comprising 100 nM of 50-end fluorescein labeled (TG)25 oligonucleotide
(Integrated DNA Technology Inc.) and 2 M of CA–NC protein, using Buffer A.
Assembly reactions were incubated for 2 h at room temperature and non-
immobilized material was removed by washing 80 l/well with Buffer A. Test
compounds, serially diluted in Buffer A + 0.125% DMSO, were added to the
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l
l/well of Buffer A (50 mM Tris pH 8.0; 350 mM
l
M
l
g/ml BSA; 1 mM DTT).
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Humbert, M.; Findlow, S.; Bodem, J.; Muller, B.; Dietrich, U.; Werner, J.;
Krausslich, H. G. Nat. Struct. Mol. Biol. 2005, 12, 671; (j) Ternois, F.; Sticht, J.;
Duquerroy, S.; Krausslich, H. G.; Rey, F. A. Nat. Struct. Mol. Biol. 2005, 12, 678;
(k) Tang, C.; Loeliger, E.; Kinde, I.; Kyere, S.; Mayo, K.; Barklis, E.; Sun, Y.; Huang,
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l
l
l
l
l
minutes prior to quantification of captured fluorescence on a Victor plate
reader (Perkin Elmer Life Sciences) equipped with fluorescein excitation and
emission filters. The capacity of a test compound to dissociate assembled
complexes was considered proportional to the observed loss of captured
fluorescence. The IC50 values for each compound were generated by fitting
disassembly curves from ten-point dilution series to the following equation:
n
n
%inhibitionððInmax ꢂ ½Iꢃ Þ ꢄ ð½Iꢃ þ ICn50ÞÞ ꢂ 100, and represent the concentration
of compound required for 50% disassembly.
12. Cytotoxicity concentration (CC50) is defined as the concentration resulting in
the death of 50 percent of the host cells and antiviral potency (EC50) as the
concentration inhibiting virus replication by 50 percent.
13. All the compounds described have a cytotoxicity window (or selectivity index)
greater than 5.
14. Beaulieu, P. L.; Haché, B.; von Moos, E. Synthesis 2003, 1683.
15. Serial dilutions of test compounds in FP buffer (50 mM Tris pH 8.0; 100 mM
NaCl; 0.0025% CHAPS; 1 mM DTT) + 2% DMSO were added (40
384-well black non-binding polystyrene plate. Reactions were completed by
adding 40 l of a solution containing CA–NC protein (40 nM) and fluorescein-
ll) to a Corning
l
labeled probe linked onto the carboxylate of 33 (40 nM) in FP buffer. Plates
were incubated for 15 minutes prior to reading on a Victor plate reader (Perkin
Elmer Life Sciences) using a fluorescence polarization protocol for fluorescein.
Control wells (absence of test compound) and blank wells (only probe) were
included on each plate, representing 0% and 100% displacement, respectively.
The IC50 values for each compound were generated by fitting displacement
curves from ten-point dilution series to the following equation:
n
n
%inhibitionððInmax ꢂ ½Iꢃ Þ ꢄ ð½Iꢃ þ ICn50ÞÞ ꢂ 100, and represent the concentration
of compound required for 50% displacement of the probe.
16. Protein Data Bank (PDB) ID:4E92.
9. Yoakim, C.; DeRoy, P.; Duplessis, M.; Gagnon, A.; Goulet, S.; Hücke, O.; Lemke,
C.; Surprenant, S. PCT Int. Appl. WO 2008/067644, 2008.