The chemokine receptor CXCR4 and its chemokine CXCL12 are involved in normal tissue patterning but also in tumor cell growth and survival as well as in the recruitment of immune and inflammatory cells, as successfully demonstrated using agents that block either CXCL12 or CXCR4. In order to achieve selectivity in drug action on the CXCR4/CXCL12 pair, in particular in the airways, drugs should be delivered as selectively as possible in the treated tissue and should not diffuse in the systemic circulation, where it may reach undesired organs. To this end, we used a previously unexploited Knoevenagel reaction to create a short lived drug, or soft drug, based on the CXCL12-neutralizing small molecule, chalcone 4, which blocks binding of CXCL12 to CXCR4. We show that the compound, carbonitrile-chalcone 4, blocks the recruitment of eosinophils to the airways in ovalbumin-sensitized and challenged mice in vivo when administered directly to the airways by the intranasal route, but not when administered systemically by the intraperitoneal route. We show that the lack of effect at a distant site is due to the rapid degradation of the molecule to inactive fragments. This approach allows selective action of the CXCL12 neutraligands although the target protein is widely distributed in the organism.
Introduction
Chemokines are small proteins that play critical roles in the development and function of various tissues in vertebrates. In the adult, they regulate the directional migration of leukocytes under normal and pathological conditions. As a rather general rule, chemokines and their G protein-coupled receptors display redundancy and binding promiscuity (i.e. several chemokines may bind to the same receptor set) (
1
), whereas a few chemokines play a pivotal and non-redundant homeostatic role. A singular case is that of the CXCL12/SDF1 chemokine and its receptor CXCR4, which are both conserved during evolution from jawless fish to humans and appear essential during normal embryogenesis and organogenesis (2
, 3
, 4
). CXCL12 is constitutively expressed by stromal, epithelial, and endothelial cells in primary lymphoid organs (including bone marrow and thymus) and secondary lymphoid organs, such as spleen and ganglia (5
). Disruption of either the CXCL12 (5
) or the CXCR4 (4
) gene is lethal during mouse embryogenesis, illustrating the prominent role of CXCL12 and CXCR4 in the patterning of embryonic tissue formation through progenitor cell migrations. Suppression of CXCL12/X4 interaction upon treatment with granulocyte(-macrophage) colony-stimulating factor (GM-CSF or G-CSF) (6
, 7
) or with the selective CXCR4 antagonist AMD 3100 promotes neutrophilia (8
). In the adult, CXCR4 and CXCL12 maintain stem cell niches in the bone marrow and contribute to the proliferation of hematopoietic progenitors (9
, - Broxmeyer H.E.
- Cooper S.
- Kohli L.
- Hangoc G.
- Lee Y.
- Mantel C.
- Clapp D.W.
- Kim C.H.
Transgenic expression of stromal cell-derived factor-1/CXC chemokine ligand 12 enhances myeloid progenitor cell survival/antiapoptosis in vitro in response to growth factor withdrawal and enhances myelopoiesis in vivo.
J. Immunol. 2003; 170: 421-429
10
).- Broxmeyer H.E.
- Orschell C.M.
- Clapp D.W.
- Hangoc G.
- Cooper S.
- Plett P.A.
- Liles W.C.
- Li X.
- Graham-Evans B.
- Campbell T.B.
- Calandra G.
- Bridger G.
- Dale D.C.
- Srour E.F.
Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist.
J. Exp. Med. 2005; 201: 1307-1318
CXCL12 and CXCR4 are also important players in pathophysiological situations (
11
, 12
, 13
, 14
), including AIDS (15
, 16
, 17
), the unusual form of neutropenia reported as WHIM syndrome (- Oberlin E.
- Amara A.
- Bachelerie F.
- Bessia C.
- Virelizier J.L.
- Arenzana-Seisdedos F.
- Schwartz O.
- Heard J.M.
- Clark-Lewis I.
- Legler D.F.
- Loetscher M.
- Baggiolini M.
- Moser B.
The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1.
Nature. 1996; 382: 833-835
18
, 19
, - Balabanian K.
- Lagane B.
- Pablos J.L.
- Laurent L.
- Planchenault T.
- Verola O.
- Lebbe C.
- Kerob D.
- Dupuy A.
- Hermine O.
- Nicolas J.F.
- Latger-Cannard V.
- Bensoussan D.
- Bordigoni P.
- Baleux F.
- Le Deist F.
- Virelizier J.L.
- Arenzana-Seisdedos F.
- Bachelerie F.
WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12.
Blood. 2005; 105: 2449-2457
20
), or carcinogenesis (11
, 14
, 21
). In addition, CXCR4 and CXCL12 are also implicated in inflammation. They contribute to promoting transendothelial migration of lymphocytes (- Chow K.Y.
- Brotin É.
- Ben Khalifa Y.
- Carthagena L.
- Teissier S.
- Danckaert A.
- Galzi J.L.
- Arenzana-Seisdedos F.
- Thierry F.
- Bachelerie F.
A pivotal role for CXCL12 signaling in HPV-mediated transformation of keratinocytes. Clues to understanding HPV-pathogenesis in WHIM syndrome.
Cell Host Microbe. 2010; 8: 523-533
22
) and invasion of inflamed tissues, as illustrated in the airways of animal models of asthma (23
, 24
, 25
, 26
, - Hachet-Haas M.
- Balabanian K.
- Rohmer F.
- Pons F.
- Franchet C.
- Lecat S.
- Chow K.Y.
- Dagher R.
- Gizzi P.
- Didier B.
- Lagane B.
- Kellenberger E.
- Bonnet D.
- Baleux F.
- Haiech J.
- Parmentier M.
- Frossard N.
- Arenzana-Seisdedos F.
- Hibert M.
- Galzi J.L.
Small neutralizing molecules to inhibit actions of the chemokine CXCL12.
J. Biol. Chem. 2008; 283: 23189-23199
27
), in the pulmonary vasculature in pulmonary arterial hypertension (28
), and in fibroproliferative tissue in a murine model of obliterative bronchiolitis after heterotopic tracheal transplantation (- Montani D.
- Perros F.
- Gambaryan N.
- Girerd B.
- Dorfmuller P.
- Price L.C.
- Huertas A.
- Hammad H.
- Lambrecht B.
- Simonneau G.
- Launay J.M.
- Cohen-Kaminsky S.
- Humbert M.
C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension.
Am. J. Respir. Crit. Care Med. 2011; 184: 116-123
29
).CXCL12 and CXCR4 were long thought to be the exclusive interactors of each other until the recent discovery that the orphan G protein-coupled receptor, CXCR7, also binds CXCL12 as well as CXCL11 (
30
, 31
). CXCR7 is expressed by endothelial cells and cardiomyocytes and is essential in heart development (- Burns J.M.
- Summers B.C.
- Wang Y.
- Melikian A.
- Berahovich R.
- Miao Z.
- Penfold M.E.
- Sunshine M.J.
- Littman D.R.
- Kuo C.J.
- Wei K.
- McMaster B.E.
- Wright K.
- Howard M.C.
- Schall T.J.
A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development.
J. Exp. Med. 2006; 203: 2201-2213
32
, 33
). CXCR7 does not elicit clear responses to CXCL12 but clearly associates with the CXCR4 protein to modulate its sensitivity for CXCL12 (- Sierro F.
- Biben C.
- Martínez-Muñoz L.
- Mellado M.
- Ransohoff R.M.
- Li M.
- Woehl B.
- Leung H.
- Groom J.
- Batten M.
- Harvey R.P.
- Martínez-A C.
- Mackay C.R.
- Mackay F.
Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7.
Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 14759-14764
33
, - Sierro F.
- Biben C.
- Martínez-Muñoz L.
- Mellado M.
- Ransohoff R.M.
- Li M.
- Woehl B.
- Leung H.
- Groom J.
- Batten M.
- Harvey R.P.
- Martínez-A C.
- Mackay C.R.
- Mackay F.
Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7.
Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 14759-14764
34
).The physiological and pathophysiological importance of CXCL12, CXCR4, and CXCR7 has prompted the launching of drug discovery programs aiming at blocking HIV entry, inhibiting cancer cell proliferation, or reducing inflammatory responses. The most advanced compound is the CXCR4 antagonist AMD 3100, which has been approved for treatment of lymphoproliferative disorders (Plerixafor®). It displays efficacy in humans in mobilizing CXCR4+ progenitor cells (
10
, - Broxmeyer H.E.
- Orschell C.M.
- Clapp D.W.
- Hangoc G.
- Cooper S.
- Plett P.A.
- Liles W.C.
- Li X.
- Graham-Evans B.
- Campbell T.B.
- Calandra G.
- Bridger G.
- Dale D.C.
- Srour E.F.
Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist.
J. Exp. Med. 2005; 201: 1307-1318
35
, 36
, 37
, 38
) upon acute administration. Use of AMD 3100 is currently being evaluated for other therapeutic indications, such as glioblastoma and the WHIM syndrome (- Liles W.C.
- Rodger E.
- Broxmeyer H.E.
- Dehner C.
- Badel K.
- Calandra G.
- Christensen J.
- Wood B.
- Price T.H.
- Dale D.C.
Augmented mobilization and collection of CD34+ hematopoietic cells from normal human volunteers stimulated with granulocyte-colony-stimulating factor by single-dose administration of AMD3100, a CXCR4 antagonist.
Transfusion. 2005; 45: 295-300
39
, - McDermott D.H.
- Liu Q.
- Ulrick J.
- Kwatemaa N.
- Anaya-O'Brien S.
- Penzak S.R.
- Filho J.O.
- Long Priel D.A.
- Kelly C.
- Garofalo M.
- Littel P.
- Marquesen M.M.
- Hilligoss D.
- Decastro R.
- Fleisher T.A.
- Kuhns D.B.
- Malech H.L.
- Murphy P.M.
The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome.
Blood. 2011; 118: 4957-4962
40
). It is, however, endowed with side effects, mainly cardiotoxicity (- McDermott D.H.
- Lopez J.
- Deng F.
- Liu Q.
- Ojode T.
- Chen H.
- Ulrick J.
- Kwatemaa N.
- Kelly C.
- Anaya-O'Brien S.
- Garofalo M.
- Marquesen M.
- Hilligoss D.
- DeCastro R.
- Malech H.L.
- Murphy P.M.
AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome.
J. Cell Mol. Med. 2011; 15: 2071-2081
41
), which is an expected problem if one considers the multiplicity of tissues expressing CXCR4 as well as the variety of diseases in which CXCR4 is implicated. According to a recent report (- Hendrix C.W.
- Collier A.C.
- Lederman M.M.
- Schols D.
- Pollard R.B.
- Brown S.
- Jackson J.B.
- Coombs R.W.
- Glesby M.J.
- Flexner C.W.
- Bridger G.J.
- Badel K.
- MacFarland R.T.
- Henson G.W.
- Calandra G.
Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection.
J. Acquir. Immune Defic. Syndr. 2004; 37: 1253-1262
42
), AMD 3100 is presumed to act as an agonist of the CXCR7 receptor, a property that might account for potential secondary effects of AMD 3100.An alternative strategy consists in preventing the agonist-receptor interaction by neutralizing the endogenous ligands. In this context, we have identified a compound that belongs to this category of pharmacological agents (i.e. a small neutralizing compound binding to CXCL12), chalcone 4 (Scheme 1), which prevents CXCL12 binding either to CXCR4 or CXCR7 (
21
, - Chow K.Y.
- Brotin É.
- Ben Khalifa Y.
- Carthagena L.
- Teissier S.
- Danckaert A.
- Galzi J.L.
- Arenzana-Seisdedos F.
- Thierry F.
- Bachelerie F.
A pivotal role for CXCL12 signaling in HPV-mediated transformation of keratinocytes. Clues to understanding HPV-pathogenesis in WHIM syndrome.
Cell Host Microbe. 2010; 8: 523-533
23
, 24
, 26
, - Hachet-Haas M.
- Balabanian K.
- Rohmer F.
- Pons F.
- Franchet C.
- Lecat S.
- Chow K.Y.
- Dagher R.
- Gizzi P.
- Didier B.
- Lagane B.
- Kellenberger E.
- Bonnet D.
- Baleux F.
- Haiech J.
- Parmentier M.
- Frossard N.
- Arenzana-Seisdedos F.
- Hibert M.
- Galzi J.L.
Small neutralizing molecules to inhibit actions of the chemokine CXCL12.
J. Biol. Chem. 2008; 283: 23189-23199
43
, 44
). Chalcone 4 blocks responses of CXCR4 to CXCL12 in vitro without affecting the basal level receptor activity and displays anti-inflammatory effects in a murine model of asthma in vivo.
SCHEME 1A, synthesis of CN-chalcone 4 (CN-Chalc4) following a Knoevenagel condensation of pCBA with 3-methoxy-4-(methoxymethyloxy)benzaldehyde (VanP). B, structure of reference compounds chalcone 4 (Chalc 4) and unsubstituted chalcone (Chalc 1).
In order to favor desired local anti-inflammatory action of the neutraligand at the expense of undesired distant effects, we explored the possibility of generating a short lived neutraligand prone to efficient biodegradation before it distributes in the body and reaches unwanted tissues. To this end, we describe here the synthesis of a molecule using previously unexploited Knoevenagel/retro-Knoevenagel reactions to generate so called soft drugs or antedrugs (
45
). Characterization of the functional properties of the new short lived carbonitrile-chalcone, in vitro and in vivo, shows that it is active when administered locally and inactive after systemic administration.DISCUSSION
Our results show the anti-inflammatory effect of a rapidly hydrolyzable CXCL12 neutraligand in an airway hypereosinophilia model. Carbonitrile-chalcone 4 is an efficient blocker of CXCL12 binding to CXCR4 and of the associated inhibition of cAMP production. However, in biological fluids, CN-chalcone 4 is rapidly degraded into two inactive metabolites, vanillin and pCBA, the two compounds that served as synthetic building blocks for its production. When administered locally in the airways by the intranasal route, CN-chalcone 4 efficiently inhibits eosinophil, neutrophil, and T cell recruitment at a low dose. By contrast, it remains without any anti-inflammatory effect in the airways when administered systemically by the intraperitoneal route even at doses 100–1000-fold higher. This is opposed to the systemic effect of chalcone 4 and demonstrates that CN-chalcone 4 behaves as an antedrug or soft drug acting at the administration site that is degraded prior to wider distribution.
Three groups, including ours (
24
, 25
, 26
, - Hachet-Haas M.
- Balabanian K.
- Rohmer F.
- Pons F.
- Franchet C.
- Lecat S.
- Chow K.Y.
- Dagher R.
- Gizzi P.
- Didier B.
- Lagane B.
- Kellenberger E.
- Bonnet D.
- Baleux F.
- Haiech J.
- Parmentier M.
- Frossard N.
- Arenzana-Seisdedos F.
- Hibert M.
- Galzi J.L.
Small neutralizing molecules to inhibit actions of the chemokine CXCL12.
J. Biol. Chem. 2008; 283: 23189-23199
27
), described that when CXCR4 signaling is inhibited, either with antibodies (25
), with CXCR4 antagonists (27
), or with CXCL12-neutralizing small molecules (26
), invasion of lungs by eosinophils is reduced by ∼50%. This piece of evidence highlights a functional role of CXCR4 and of its ligand either in the allergic response onset or in its maintenance. The question as to whether airway inflammation stimulates CXCL12 production continues to be debated because immunohistochemical detection in lung tissue shows no change (- Hachet-Haas M.
- Balabanian K.
- Rohmer F.
- Pons F.
- Franchet C.
- Lecat S.
- Chow K.Y.
- Dagher R.
- Gizzi P.
- Didier B.
- Lagane B.
- Kellenberger E.
- Bonnet D.
- Baleux F.
- Haiech J.
- Parmentier M.
- Frossard N.
- Arenzana-Seisdedos F.
- Hibert M.
- Galzi J.L.
Small neutralizing molecules to inhibit actions of the chemokine CXCL12.
J. Biol. Chem. 2008; 283: 23189-23199
25
), whereas immunochemical determination in BALF (49
) and gene expression in lung (50
) indicate that CXCL12 is up-regulated. The expression of CXCR4, on the other hand, is higher in BAL CD4+ T cells of human asthmatics as compared with their peripheral blood CD4+ lymphocytes (51
) and is up-regulated by the proinflammatory cytokine IL-4 in CD4+ T cells, including Th2 cells (25
, 52
, 53
, 54
). This renders significant response to CXCL12 likely to occur in the airway, whatever the regulation of CXCL12 expression. In addition, CXCR4 is also expressed in eosinophils (55
, 56
). Eosinophils have a migratory response to CXCL12 comparable with that evoked by eotaxin.The mode of action of neutraligands opens the way to new therapeutic strategies especially for airway diseases, because (i) chalcone 4 and its analogs are active through the intranasal route, and (ii) they act on a new target, namely CXCL12, the ligand of CXCR4 and CXCR7 chemokine receptors. Thus, the mode of action of chalcone 4 (
26
) and its analogs chalcone 4-phosphate (- Hachet-Haas M.
- Balabanian K.
- Rohmer F.
- Pons F.
- Franchet C.
- Lecat S.
- Chow K.Y.
- Dagher R.
- Gizzi P.
- Didier B.
- Lagane B.
- Kellenberger E.
- Bonnet D.
- Baleux F.
- Haiech J.
- Parmentier M.
- Frossard N.
- Arenzana-Seisdedos F.
- Hibert M.
- Galzi J.L.
Small neutralizing molecules to inhibit actions of the chemokine CXCL12.
J. Biol. Chem. 2008; 283: 23189-23199
24
) and CN-chalcone 4 (this work) appears as complementary to that of classical receptor antagonists because the blockade of the chemokine is without any effect on the receptor. In particular, it is neither a partial agonist of CXCR4 nor an activator of CXCR7 (42
, 57
, 58
), as was described for AMD 3100 and in other instances with RANTES (regulated on activation normal T cell expressed and secreted) analogs acting on the CCR5 receptor (59
). Therefore, the mechanism of action of chalcone 4 and its analogs deserves to be exploited in drug development programs.Another concern was raised regarding the large tissue distribution of CXCR4, which can be the cause of possible side effects of CXCR4-targeting drugs. The use of systemically administered AMD 3100 confirmed the risk of side effects resulting from general CXCR4 inhibition. This was illustrated on leukocyte maturation in the bone marrow (
27
) and on cardiac function (36
, 37
, 60
). We therefore generated a short lived readily hydrolyzable analog of the initial compound, chalcone 4, and show here that CN-chalcone 4 is as active as chalcone 4 on airway inflammation when administered by the intranasal route, whereas it is inactive when delivered systemically using the intraperitoneal route. It therefore typically behaves as an antedrug or soft drug.- Rusconi S.
- Lo Cicero M.
- Viganò O.
- Sirianni F.
- Bulgheroni E.
- Ferramosca S.
- Bencini A.
- Bianchi A.
- Ruiz L.
- Cabrera C.
- Martinez-Picado J.
- Supuran C.T.
- Galli M.
New macrocyclic amines showing activity as HIV entry inhibitors against wild type and multi-drug resistant viruses.
Molecules. 2009; 14: 1927-1937
The general principles and reactions that are used for antedrug structures include various cleavable chemical functions, such as carboxylic esters and amides, oximes, thioester, spiroenones, or lactones (
45
, 61
). In designing carbonitrile-chalcone 4, we here make use of the Knoevenagel and retro-Knovenagel reactions (62
) yielding the desired compound due to a reversible aldolization reaction (63
) that has never been exploited in the antedrug field before. The biologically active compound, carbonitrile-chalcone 4, is readily hydrolyzed in aqueous media with a half-life of a few tens of min and yields vanillin and pCBA, which both serve as synthetic building blocks for the preparation of carbonitrile-chalcone 4. The probable hydrolysis mechanism involves the addition of one water molecule according to a Michael addition on the α-β unsaturated conjugated system. Hydration of the double bond is presumably facilitated by the presence of the electron-attracting nitrile group. The resulting enolic structure then evolves toward production of the initial reactants vanillin and pCBA according to a retroaldolization reaction (64
). We show here that neither the reactants nor carbonitrile-chalcone 4 display any toxic effect in vivo or in HepG2 cells in vitro.In conclusion, our results show a strong activity of a chalcone 4 derivative, carbonitrile-chalcone 4, displaying only local and no systemic effect due to a short lifetime in biological fluids, therefore playing the role of an antedrug, which is particularly interesting when the airways are considered. The various chalcone 4 derivatives that we have generated in this and previous works will serve as tools to understand CXCR4, CXCR7, and CXCL12 functions in the airway inflammation process. In particular, the sequence of events and their dependence on CXCL12 activity will be important elements in the characterization of CXCL12 as a drug target in airway inflammation. The mechanism of action of chalcone 4 and its analogs deserves to be exploited in drug development programs because blockade of the chemokine is without any effect on the receptor spontaneous activity as opposed to the most widely encountered pharmacological action of G protein-coupled receptor antagonists.
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Article Info
Publication History
Published online: February 28, 2013
Received in revised form:
February 27,
2013
Received:
January 3,
2013
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© 2013 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.
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