Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition

Article abstract of DOI:10.1021/acsmedchemlett.5b00471

The optimization, based on computational, thermodynamic, and crystallographic data, of a series of small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120 of human immunodeficiency virus (HIV) has been achieved. Importantly, biological evaluation revealed that the small-molecule CD4 mimics (4-7) inhibit HIV-1 entry into target cells with both significantly higher potency and neutralization breadth than previous congeners, while maintaining high selectivity for the target virus. Their binding mode was characterized via thermodynamic and crystallographic studies.

Full text of DOI:10.1021/acsmedchemlett.5b00471

Letter
pubs.acs.org/acsmedchemlett
Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV‑1
Entry Inhibition
Bruno Melillo,† Shuaiyi Liang,‡ Jongwoo Park,† Arne Schon,∥ Joel R. Courter,† Judith M. LaLonde,⊥
̈
Daniel J. Wendler,† Amy M. Princiotto,# Michael S. Seaman,∇ Ernesto Freire,∥ Joseph Sodroski,#,¶,⊗
Navid Madani,# Wayne A. Hendrickson,‡,§ and Amos B. Smith, III*,†
†Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
§
‡Department of Biochemistry and Molecular Biophysics and Department of Physiology and Cellular Biophysics, Columbia
University, New York, New York 10032, United States
∥Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218, United States
⊥Department of Chemistry, Bryn Mawr College, Bryn Mawr, Pennsylvania 19010, United States
#Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, ∇Center for Virology and Vaccine Research, Beth
¶
Israel Deaconess Medical Center, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston,
Massachusetts 02115, United States
⊗Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, United States
S
* Supporting Information
ABSTRACT: The optimization, based on computational,
thermodynamic, and crystallographic data, of a series of
small-molecule ligands of the Phe43 cavity of the envelope
glycoprotein gp120 of human immunodeficiency virus (HIV)
has been achieved. Importantly, biological evaluation revealed
that the small-molecule CD4 mimics (4−7) inhibit HIV-1
entry into target cells with both significantly higher potency
and neutralization breadth than previous congeners, while
maintaining high selectivity for the target virus. Their binding
mode was characterized via thermodynamic and crystallo-
graphic studies.
KEYWORDS: HIV, gp120, CD4, entry inhibitor, structure-based drug design, thermodynamics, X-ray crystallography, viral inhibition,
protein−protein interactions
small-molecule mimics, both on the surface of the virion9 and,
ith an estimated 35 million people currently living with
WHIV-1 worldwide in conjunction with 2.1 million new more recently, on the surface of infected cells.10 Thus, in our
infections each year,1 the development of effective new
efforts to enhance the direct inhibitory activity of the small-
molecule CD4 mimetics, we have sought to improve our
understanding of the underlying molecular mechanisms.
Logically, we chose 3 as the starting point for the design of a
new generation of more potent small-molecule entry inhibitors.
Having previously conducted structural optimization on
Regions I and II of the parent scaffold, defined respectively by
the halogenated aromatic ring and the oxalamide linker (Figure
2), our efforts focused on modification of the substituted
indane ring comprising Region III.11 Importantly, the
protein:ligand cocrystal structure of 3 permitted definition of
potential binding hotspots in proximity to the aromatic portion
of the indane.4 Based on the structure and “hotspot” analysis,12
we also demonstrated that a methylene (one carbon) spacer
strategies to achieve both prevention of HIV transmission,
complementing known pre-exposure prophylactics2,3 and
depletion of the “viral reservoir” in HIV-infected patients
remain critically important challenges.
Recently, we reported the structure-based design, synthesis,
and evaluation of the small-molecule CD4-mimic DMJ-II-121
(3), a micromolar inhibitor of HIV-1YU‑2 entry into human
immune cells.4,5 Like the initial congeners reported by Debnath
et al. (see 1 and 2, Figure 1),6−8 3 binds the Phe43 cavity of the
viral envelope (Env) glycoprotein gp120, blocking CD4
binding and triggering a conformational change that ultimately
results in viral inactivation.
A particularly attractive feature of this mechanism of action
resides in the opportunity to elicit immune responses specific to
epitopes that become exposed on the surface on Env upon the
binding of CD4 mimics. Importantly, we have demonstrated
that antibodies can indeed recognize gp120 bound to the CD4
Received: December 9, 2015
Accepted: January 13, 2016
© XXXX American Chemical Society
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not result in significant loss of inhibitory activity relative to 3
(HIV-1YU‑2 IC50 6.8 μM). To determine the effect of absolute
stereoconfiguration on bioactivity, enantioenriched (+)- and
(−)-4 were prepared by separation of the ultimate synthetic
intermediate via semipreparative supercritical fluid chromatog-
raphy (SFC) employing a chiral stationary phase. Global
deprotection resulted in (+)- and (−)-4 (in >96% ee).
Evaluation of the individual enantiomers revealed that similar
to the previous enantiopure congeners, the (R,R)-stereoisomer
(+)-4 exhibited 40-fold stronger inhibitory activity than the
(S,S)-counterpart (YU-2 IC50 2.1 and 87.8 μM, respectively).
This result represents a gain, albeit modest, relative to (+)-3
(YU-2 IC50 3.8 μM). We were, however, pleased to find that
the binding affinity of (+)-4 to full-length gp120, measured by
isothermal titration calorimetry (ITC), had increased quite
significantly [KD 24 vs 110 nM for (+)-3].
Given the difference in activity between (+)- and (−)-4, the
original synthetic route was modified to permit facile
preparation of the single enantiomers of this new generation
of entry inhibitors. To this end, the enantioselective synthesis
of (+)-4 began with protection of commercially available 6-
bromoindanone (8) as the corresponding dioxolane, followed
by lithiation and formylation, to furnish aldehyde 9 (Scheme
1). Reductive amination, protection of the resulting secondary
Figure 1. NBD-556 (1), (+)-DMJ-II-121 [(+)-(R,R)-3], and their
gp120-bound X-ray structures (PDB accession codes: 3TGS and 4I53,
respectively).
Scheme 1. Enantioselective Synthesis of (+)-(R,R)-4
Figure 2. (A) Computational design of 4. (B) Further evolution of
inhibitor Region III scaffolds.
present between the indane skeleton and the guanidinium
moiety in 3 proved optimal for viral entry inhibition;4 therefore,
no modifications were planned in that section of Region III.
Instead, a virtual fragment growing algorithm,13 followed by
docking,14,15 was carried out to establish contacts between the
potentially new analogues and “hotspot” gp120Gly472, a highly
conserved gp120 residue located in the outer domain near the
vestibule of the Phe43 cavity, associated with moderate Env
restructuring (i.e., allosteric signal) upon CD4 binding.12,16
This computational analysis suggested that addition of a
(methylamino)methyl unit at position 6 of the indane skeleton
(see 4, Figure 2) might result in hydrogen bonding with the
backbone carbonyl of gp120Gly472. Our computational model
also predicted binding between the guanidinium terminus and
gp120Asp368, an interaction that had been predicted by our prior
modeling work, but to date had proven elusive.5
amine as the corresponding Boc carbamate, and selective
removal of carbonyl protection then revealed indanone 10, now
bearing the desired (methylamino)methyl functionality. Ketone
10 was next carboxylated at the α-position, and the resulting
racemic ketoester ( )-11 subjected to dynamic-kinetic
resolution employing chiral ruthenium catalyst RuCl(p-
cymene)[Ts-DPEN],17 which permitted transfer hydrogenation
with excellent stereoselectivity (er 99:1), as demonstrated by
chiral phase SFC. This transformation was carried out
employing both enantiomers of the ruthenium catalyst, thus
permitting access to both enantiomers of β-hydroxyester 12.
Each enantiomer was then taken through the following
identical sequence. Exhaustive reduction of (+)-12, initially
To evaluate in rapid fashion the biological impact of this
previously unexplored scaffold substitution pattern, the syn-
thesis of the (methylamino)methyl-bearing analogue JP-III-048
(4) was carried out initially in racemic form (see Supporting
Information). Pleasingly, a viral infectivity assay employing
( )-4 revealed that the proposed structural modification did
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Table 1. Small-Molecule CD4Mimics: Inhibition of Viral Entry and Protein−Ligand Affinity
a
b
The IC50 was determined in Cf2Th-CD4/CCR5 cells infected with HIV-1 virus of the strains indicated. The IC50 in cells infected with HIV-1
c
pseudotyped with the envelope glycoproteins of amphotropic murine leukemia virus (A-MLV). As deemed by ITC employing YU-2 gp120.
d
Energies in kcal/mol.
utilizing sodium borohydride in methanol, resulted in partial
epimerization (cis/trans ≈ 3:1). Pleasingly, treatment of (+)-12
with the more reactive lithium aluminum hydride in an aprotic
solvent (THF) provided the desired diol as a single
stereoisomer. Selective silylation of the primary hydroxyl
followed by treatment with diphenylphosphorylazide provided
the corresponding azide with complete inversion of stereo-
chemistry at the benzylic position. Palladium-catalyzed hydro-
genation next furnished amine (+)-13. Following union with
oxalic acid 14, fluoride-mediated removal of the silyl group
furnished the corresponding primary alcohol, which in turn was
subjected to Mitsunobu conditions18 to install the requisite
guanidine functionality and reveal, after treatment with
trifluoroacetic acid, target inhibitor (+)-(R,R)-4 as the
corresponding bis(trifluoroacetate) salt. Gratifyingly, the
synthetic route proved highly efficient, furnishing the target
compound in 20% yield over 15 steps from commercially
available 6-bromoindanone (8, Scheme 1). The alternate
enantiomer (−)-(S,S)-4 was synthesized in identical manner
from (−)-12.
synthetic fashion, readily furnished the target compounds
(+)-(R,R)- and (−)-(S,S)-5 (Figure 2).
Although (+)-(R,R)-5 displayed only a modest improvement
in activity against HIV-1 monotropic strains YU2 and ADA
(clone AD8) (IC50 1.5 and 6.4 μM, respectively), a 5-fold
increase in potency relative to congener 3 was observed against
strain JR-FL (IC50 14.2 μM). Again, however, (−)-(S,S)-5
displayed a lower level of viral entry inhibition (JR-FL IC50
>
100 μM, Table 1). The neutralization breadths of the more
potent CD4 mimics, specifically (+)-(R,R)-4 and (+)-(R,R)-5,
were measured against a panel of 52 HIV-1 Env pseudoviruses.
Like for previous congeners,4 clade B pseudoviruses were the
most sensitive to the new inhibitors (9/9 strains were
neutralized), with also significant activity in clades C (11/17)
and D (3/3). While both assayed compounds demonstrated
similar inhibitory profiles, (+)-(R,R)-5 exhibited 1.3-to-1.8-fold
lower geometric mean titer (GMT) inhibitory concentrations
than (+)-(R,R)-4 in clades B (GMT IC50 3.5 μM) and C
(GMT IC50 17 μM), thus corroborating the trend observed
with individual strains (see Supporting Information for further
details).
To understand the structural basis of the increased
bioactivity, (+)-(R,R)-4 was soaked into preformed crystals of
gp120 from HIV Clade C1086,19 and diffraction data was
obtained at 2.7 Å Bragg spacings (see Supporting Information).
The resulting protein:ligand structure revealed that, compared
to (+)-(R,R)-3 entry inhibitor, (+)-(R,R)-4 establishes two
additional hydrogen-bonding interactions, one with the back-
bone carbonyl of gp120Gly431 and another with the carbonyl of
gp120Gly472, in agreement with our computational prediction.
Disappointingly, however, (+)-(R,R)-4 failed to bind
gp120Asp368. Instead, as in the case of (+)-(R,R)-3,4 the
guanidinium terminus interacts with the backbone carbonyl of
gp120 Met426. Considering (i) the diverse nature of the hotspots
located in proximity to the Phe43 cavity (i.e., their varying
contributions to the global allosteric signal upon binding of
CD4), and (ii) the proximity of the ligand’s guanidinium to the
still elusive gp120Asp368, we reasoned that subtle structural
modifications resulting in changes in ligand orientation might
significantly impact bioactivity. We thus set out to prepare
analogues now bearing the (methylamino)methyl moiety at
indane position 5 (see 5, Figure 2). The route described above,
in this case employing commercially available 5-bromoinda-
none (see Supporting Information for details) in similar
However, when we turned to ITC to evaluate the binding
affinities of these new analogues, we discovered that, although
more active against viral entry, (+)-(R,R)-5 binds monomeric
gp120 with a lower affinity than (+)-(R,R)-4 (KD 47 vs 24 nM).
Interestingly, compared to the immediate predecessor,
(+)-(R,R)-5 elicits a lowered entropic penalty (−TΔS =
+10.7 kcal/mol vs − TΔS = +17.8 kcal/mol, Table 1). The
difference in thermodynamic signatures between (+)-(R,R)-4
and (+)-(R,R)-5 upon binding gp120 suggests that subtle
structural differences (e.g., in this case, position isomerism)
could be responsible for inducing significantly dissimilar
binding modes, a hypothesis we again sought to evaluate
crystallographically.
The resulting structure of gp120-bound (+)-(R,R)-5,
obtained employing the same technique as described above
(see Supporting Information), revealed a generally similar
binding pose to that of (+)-(R,R)-4. Orientations for the indane
rings differ slightly such that the substituent projects into much
of the same space despite being moved from position 5 to
position 6. Nevertheless, the hydrogen bond from the
(methyamino) methyl group to the carbonyl of gp120Gly472 is
now lost [dN−O = 3.65 Å in 5 vs 3.08 Å in 4]. This change may
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explain the decreased enthalpic contribution to the binding
energy (Table 1). The observations derived from the structure
of (+)-(R,R)-5:gp120 with perhaps more immediate practical
implications was the proximity of the ligand’s (methylamino)-
methyl side-chain to gp120Asp474, a CD4 binding hotspot
associated with a purely enthalpic signal.12 To exploit this
feature we directly converted the secondary amine in
(+)-(R,R)-5 to a guanidinium moiety, which would in effect
extend the reach of the side-chain and in turn potentially
establish a strong interaction with the nearby carboxylate of
gp120Asp474. Pleasingly, selective incorporation of the new
guanidine functionality could be readily achieved in one step by
subjecting (+)-(R,R)-5 to 1H-pyrazol-1-carboxamidine hydro-
chloride, to furnish (+)-(R,R)-6 (see Supporting Information).
To our delight, (+)-(R,R)-6 inhibited infection of HIV-1 at
lower concentrations than all previous analogues in all tested
strains (Figure 3; YU‑2IC50 0.8 μM; JR‑FLIC50 6.2 μM; AD8IC50 3.3
Figure 4. Comparison of gp120-bound poses of 4 (A), 5 (B), 6 (C),
and 7 (D), all (R,R)-series. Orientations are the same based on
superpositioning of gp120 Cα positions. Hydrogen-bond interactions
are shown as dashed lines.
bonding (dN−O = 3.05 Å for 6 and 3.21 Å for 7 as compared to
3.3−3.4 Å for 4 and 5).
Although the disparity between potency and protein affinity
still remains an unresolved paradox, a possible explanation lies
in that thermodynamic measurements employ monomeric
gp120, which only comprises part of the fully functional Env (a
trimer of gp41-gp120). Indeed, interactions of the more potent
inhibitors and the trimeric functional Env might also entail
interactions between the Env protomers themselves that in vitro
assays employing monomeric gp120 would not reveal.
Logically, nonetheless, thermodynamic data are in agreement
with crystallographic data, also obtained on monomeric
glycoprotein.
In summary, the design of a more potent and more broadly
active small molecule CD4-mimetic inhibitor of HIV-1
infection has been achieved exploiting structural and
thermodynamic data. In particular, (+)-(R,R)-6 exhibited 1
order of magnitude improvement in inhibitory potency, over
our last generation of compounds, against the neutralization-
resistant HIV-1 strain JR-FL. Virus neutralization strategies
employing these new constructs, in addition to direct viral entry
inhibition, are currently being explored and will be reported in
due course. These strategies rely on the unique ability of the
CD4-mimetic inhibitors to expose, upon Env binding, epitopes
recognized by antibodies present in HIV-infected individu-
als.9,10 That we have already demonstrated the capability of the
earlier congeners of (+)-(R,R)-6, namely, 3 and 4, to enhance
the efficacy of immune responses both against the HIV virus
itself7 and against infected cells10 is very encouraging.
Figure 3. Effect of (+)-(R,R)-4 (JP-III-048) and (+)-(R,R)-6 (BNM-
IV-147) on the infection of Cf2Th-CD4-CCR5 cells by recombinant,
luciferase-expressing HIV-1 pseudoviruses carrying envelope glyco-
proteins of the YU2 or JR-FL strains or that of the amphotropic
murine leukemia virus (AMLV, negative control). Virus infection is
expressed as the percentage of infection (measured by luciferase
activity in the target cells) observed in the presence of increasing
concentrations of compound relative to the level of infection observed
in the absence of compound.
μM; Table 1). Interestingly, however, the binding affinity of
(+)-(R,R)-6 for monomeric gp120 again appeared to decrease
relative to the less potent congeners (+)-(R,R)-4 and
(+)-(R,R)-5. In turn, the diguanidinium congener (−)-(R,R)-
7, prepared in a similar fashion from (+)-(R,R)-4, exhibiting a
thermodynamic profile nearly identical to that of (+)-(R,R)-6,
proved to be approximately half as potent (see Table 1).
Crystal structures were also determined for gp120 complexes
with (+)-(R,R)-6 and with (−)-(R,R)-7. The binding poses for
these (methylguanidino) methyl derivatives are almost the
same as those for their (methylamino) methyl congeners,
(+)-(R,R)-4 and 5 (Figure 4); however, the added guanidine
moieties point away from possible hydrogen-bonding partners,
including gp120Asp474. For all four complexes, there are
hydrogen bonds from the guanidinium group at indane
position 1 to the carbonyl groups of gp120Met426 and
gp120Gly431. For (+)-(R,R)-6 and (−)-(R,R)-7, distances to
the carbonyl oxygen of gp120Glu429 suggest additional hydrogen
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00471.
■
S
Synthesis, experimental methods and crystallographic
data (PDF)
Accession Codes
Accession Codes Coordinates and structure factors have been
deposited in the Protein Data Bank with the following
accession numbers: 5F4L, 5F4P, 5F4R, and 5F4U.
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(6) Zhao, Q.; Ma, L.; Jiang, S.; Lu, H.; Liu, S.; He, Y.; Strick, N.;
Neamati, N.; Debnath, A. K. Identification of N-Phenyl-N′-(2,2,6,6-
tetramethyl-piperidin-4-yl)-oxalamides as a New Class of HIV-1 Entry
Inhibitors that Prevent gp120 Binding to CD4. Virology 2005, 339,
213−225.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: smithab@sas.upenn.edu. Phone: 215-898-4860.
Present Addresses
(7) For recent work by Debnath et al. in the area of HIV entry
inhibitors see: Curreli, F.; Kwon, Y.; Zhang, H.; Scacalossi, D.; Belov,
D. S.; Tikhonov, A. A.; Andreev, I. A.; Altieri, A.; Kurkin, A. V.;
Kwong, P. D.; Debnath, A. K. Structure-Based Design of a Small
Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity.
J. Med. Chem. 2015, 58, 6909−6927.
(8) Curreli, F.; Haque, K.; Xie, L.; Qiu, Q.; Xu, J.; Yong, W.; Tong,
X.; Debnath, A. K. Synthesis, Antiviral Activity and Resistance of a
Novel Small Molecule HIV-1 Entry Inhibitor. Bioorg. Med. Chem.
2015, 23, 7618.
J.P.: LG Chem, Daejeon, South Korea.
J.R.C.: Seattle Genetics, Bothell, Washington 98021, United
States.
J.M.L.: Teva Pharmaceuticals USA Inc., Horsham, Pennsylvania
19044, United States.
D.J.W.: Max Planck Florida Institute for Neuroscience, Jupiter,
Florida 33458, United States.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
(9) Madani, N.; Princiotto, A. M.; Schon, A.; LaLonde, J.; Feng, Y.;
̈
Freire, E.; Park, J.; Courter, J. R.; Jones, D. M.; Robinson, J.; Liao, H.-
X.; Moody, M. A.; Permar, S.; Haynes, B.; Smith, A. B.; Wyatt, R.;
Sodroski, J. CD4-Mimetic Small Molecules Sensitize Human
Immunodeficiency Virus to Vaccine-Elicited Antibodies. J. Virol.
2014, 88, 6542−6555.
Funding
Funding was provided by a Program Project (NIH GM 56550)
to J.L., E.F., W.A.H., A.B.S., and J.S.
(10) Richard, J.; Veillette, M.; Brassard, N.; Iyer, S. S.; Roger, M.;
Notes
Martin, L.; Pazgier, M.; Schon, A.; Freire, E.; Routy, J.-P.; Smith, A. B.,
̈
The authors declare no competing financial interest.
III; Park, J.; Jones, D. M.; Courter, J. R.; Melillo, B. N.; Kaufmann, D.
E.; Hahn, B. H.; Permar, S. R.; Haynes, B. F.; Madani, N.; Sodroski, J.
G.; Finzi, A. CD4Mimetics Sensitize HIV-1-Infected Cells to ADCC.
Proc. Natl. Acad. Sci. U. S. A. 2015, 112, E2687−E2694.
ACKNOWLEDGMENTS
■
We thank Irwin Chaiken and all the members of the P01
Consortium Structure-Based Antagonism of HIV-1 Envelope
Function in Cell Entry. Dr. Rakesh Kohli, and Drs. George
Furst and Jun Gu (University of Pennsylvania) are also
acknowledged for their assistance obtaining mass and NMR
spectra, respectively.
(11) For efforts by Tamamura et al. toward the optimization of CD4-
mimetic HIV entry inhibitors, in particular via modification of the so-
called Region III, see: Mizuguchi, T.; Harada, S.; Miura, T.; Ohashi,
N.; Narumi, T.; Mori, H.; Irahara, Y.; Yamada, Y.; Nomura, W.;
Matsushita, S.; Yoshimura, K.; Tamamura, H. A Minimally Cytotoxic
CD4Mimic as an HIV Entry Inhibitor. Bioorg. Med. Chem. Lett. 2016,
26, 397−400 and refs cited therein.
(12) Liu, Y.; Schon, A.; Freire, E. Optimization of CD4/gp120
̈
ABBREVIATIONS
■
Inhibitors by Thermodynamic-Guided Alanine-Scanning Mutagenesis.
Chem. Biol. Drug Des. 2013, 81, 72−78.
HIV-1, human immunodeficiency virus type 1; SIV, simian
immunodeficiency virus; sCD4, soluble CD4; ITC, isothermal
titration calorimetry; A-MLV, amphotropic murine leukemia
virus; GMT, geometric mean titer; THF, tetrahydrofuran; Boc,
tert-butoxycarbonyl; HMDS, hexamethyldisilazide; DPEN,
diphenylethylenediamine; TBS, tert-butyldimethylsilyl; DPPA,
diphenylphosphorylazide; DBU, 1,8-diazabicyclo[5.4.0]undec-
7-ene; TBTU, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethy-
luronium tetrafluoroborate; DIPEA, diisopropylethyl amine;
TBAF, tributylammonium fluoride; DEAD, diethylazodicarbox-
ylate; TFA, trifluoroacetic acid
(13) Molecular Operating Environment (MOE), 2012.10; Chemical
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Proteins: Struct., Funct., Genet. 2003, 52, 609−623.
(16) Kwong, P. D.; Wyatt, R.; Robinson, J.; Sweet, R. W.; Sodroski,
J.; Hendrickson, W. A. Structure of an HIV gp120 Envelope
Glycoprotein in Complex with the CD4 Receptor and a Neutralizing
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