EP4351587A1 - Sterol derivatives as new dectin-1 receptor ligands in the therapeutic treatment of diseases related to said receptor - Google Patents
Sterol derivatives as new dectin-1 receptor ligands in the therapeutic treatment of diseases related to said receptorInfo
- Publication number
- EP4351587A1 EP4351587A1 EP22735029.5A EP22735029A EP4351587A1 EP 4351587 A1 EP4351587 A1 EP 4351587A1 EP 22735029 A EP22735029 A EP 22735029A EP 4351587 A1 EP4351587 A1 EP 4351587A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- group
- opo
- dectin
- oso
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention originates in the pharmaceutical field and relates in particular to the use of sterol derivatives as Dectin-1 receptor ligands in the prevention and treatment of diseases related to said receptor.
- the invention also refers to compositions and uses of such sterol derivatives as immunostimulants for the prevention and treatment of fungal diseases, widespread inflammatory diseases related to pathogenic infections and autoimmune responses, as well as tumors.
- the immune system recognizes and responds to pathogens through the so-called ‘antigen presenting cells’ (APC), which play a fundamental role in controlling the interface of innate and acquired immunity by activating the cascade of intra- and inter-cellular signals.
- APC antigen presenting cells
- PRRs pattern recognition receptors
- TLR toll-like receptors
- CLR C-type-lectin
- NLR NOD-like
- RLR RIG-l-like receptors
- PAMP pathogen-associated molecular patterns
- DAMP cell damage-associated molecular patterns
- APCs including macrophages and dendritic cells (DCs)
- DCs dendritic cells
- PRRs are therefore therapeutic targets as they can be ‘exploited’ by their natural and/or artificial ligands, in order to activate the immune defenses and modulate them in order to provide adequate protection to the body.
- Immune cell receptors ligands may consequently have great clinical potential for the development of therapies aimed at the resolution of various diseases.
- CLRs after TLRs, represent the second most important class of PRRs capable of activating APCs and developing a robust Th1 and Th17 response that makes these receptors potential targets of anti-infectious vaccines adjuvants and capable of orchestrating adequate and balanced immunogenic response.
- CLRs CLRs to interact (cross-talk) with other families of PRR receptors such as TLRs, by amplifying and/or down-regulating their inflammatory responses, thus highlighting the ability to modulate the immunogenic response in such a way that this is effective, by favoring a ‘fine tuning’ necessary to avoid harmful and/or autoimmune reactions (Brown, G.D.; Willment, J.A.; Whitehead, L. C-type lectins in immunity and homeostasis. Nat. Rev. Immunol. 2018, 18(6), 374-389).
- CLRs functions are therefore essential for cellular immunity and homeostasis.
- This family of receptors consists of over 1000 proteins divided into 17 groups based on their structure and/or function.
- Dectin-1 (CLEC-7A) is one of the most studied and characterized CLR receptors and is mainly expressed on myeloid cells, including monocytes, macrophages, DCs, and neutrophils ((a) Brown, G.D.; Crocker, P.R. Lectin Receptors Expressed on Myeloid Cells. Microbiol. Spectr. 2016, 4(5), doi: 10.1128/microbiolspecMCHD- 0036-2016;
- Dectin-1 plays a key role in anti fungal immunity, as it recognizes numerous fungal species including pathogens such as Candida albicans, Aspergillus fumigatus, Coccidioides immitis and Pneumocystis carinii ((a)Hardison, S.E.; Brown, G.D. C-type lectin receptors orchestrate antifungal immunity. Nat. Immunol. 2012, 13(9), 817-22; (b) Viriyakosol, S.; Jimenez, M.P.; Gurney, M.A.; Ashbaugh, M.E.; Fierer, J.
- pathogens such as Candida albicans, Aspergillus fumigatus, Coccidioides immitis and Pneumocystis carinii ((a)Hardison, S.E.; Brown, G.D. C-type lectin receptors orchestrate antifungal immunity. Nat. Immunol. 2012, 13(9), 817
- Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice. Mbio. Asm Org. 2013, 4(1), e00597- 12). Gene variations of human Dectin-1 can also translate into increased susceptibility to infections with A. fumigatus, Trichophyton rubrum and C.
- albicans ((a) Ferwerda, B.; Ferwerda, G.; Plantinga, T.S.; Willment, J.A.; Van Spriel, A.B.; Venselaar, H.; Elbers, C.C.; Johnson, M.D.; Cambi, A.; Huysamen, C.; Jacobs, L; Jansen, T.; Verheijen, K.; Masthoff, L.; Morre, S.A.; Vriend, G.; Williams, D.L.; Perfect, J.R.; Joosten, L.A.; Wijmenga, C.; Van der Meer, J.W.; Adema, G.J.; Kullberg, B.J.; Brown, G.D.; Netea, M.G.
- Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor- dependent mechanisms of antifungal immunity. Blood 2010, 116(24), 5394-5402). Ligand recognition by Dectin-1 can trigger and regulate numerous cellular responses, including phagocytosis, autophagy, DC maturation, and cytokine and chemokine production.
- Dectin-1 plays a much larger role in immunity, with the ability to recognize other types of pathogens including Haemophilus influenzae, Salmonella typhimurium, Mycobacterium tuberculosis and Leishmania infantum ((a) Drummond, R.A.; Brown, G.D. Signalling C-Type Lectins in Antimicrobial Immunity. PLoS Pathog.
- Dectin-1 is able to determine the development of adaptive immune responses by differentiating Th1 and Th17 responses ((a) Drummond, R.A; Brown, G.D. The role of Dectin-1 in the host defence against fungal infections. Curr. Opin. Microbiol. 2011, 14(4), 392-9; (b) LeibundGut-Landmann, S.; Gross, O.; Robinson, M.J,.; Osorio, F.; Slack, E.C.; Tsoni, S.V.; Schweighoffer, E.; Tybulewicz, V.; Brown, G.D.; Ruland, J.; Reis e Sousa, C.
- This receptor also promotes humoral responses via Th2 (Kaisar, M.; Ritter, M.; Del Fresno, C.; Jonasdottir, H.S.; Van der Ham, A.J.; Pelgrom, L.R.; Schramm, G.; Layland, L.E.; Sancho, D.; Da Costa, C.P.; Giera, M.; Yazdanbakhsh, M.; Everts B. Dectin-1 /2-induced autocrine PGE2 signaling licenses dendritic cells to prime Th2 responses.
- Th2 Kerman, M.; Ritter, M.; Del Fresno, C.; Jonasdottir, H.S.; Van der Ham, A.J.; Pelgrom, L.R.; Schramm, G.; Layland, L.E.; Sancho, D.; Da Costa, C.P.; Giera, M.; Yazdanbakhsh, M.; Everts B. Dectin
- Dectin-1 is also implicated in allergies and in the regulation of autoimmune diseases, such as arthritis and colitis (Yoshitomi, H.; Sakaguchi, N.; Kobayashi, K.; Brown, G.D.; Tagami, T.; Sakihama, T.; Hirota, K.; Tanaka, S.; Nomura, T.; Miki, I.; Gordon, S.; Akira, S.; Nakamura, T.; Sakaguchi, S. A role for fungal ⁇ beta ⁇ -glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J. Exp. Med.
- Dectin-1 therefore protects against chronic liver diseases by suppressing TLR 4 action, mitigating the expression of this receptor and the corresponding CD14 co-receptor. More generally, this cross-talk implies a role for Dectin-1 in the suppression of sterile inflammation, inflammation-induced oncogenesis, and LPS-mediated sepsis (Seifert, L; Deutsch, M.; Alothman, S.; Alqunaibit, D.; Werba, G.; Pansari, M.; Pergamo, M.; Ochi, A.; Torres-Femperez, A.; Levie, E.; Tippens, D.; Greco, S.H.; Tiwari, S.; Ly, N.N.G.; Eisenthal, A.; Van Fleerden, E.; Avanzi, A.; Barilla, R.; Zambirinis, C.P.; Rendon, M.; Daley, D.; Pachter, H.L.; Hajdu, C.
- Dectin-1 also plays an important role in the field of anti-tumor immunity as demonstrated by its ability to promote the differentiation of Th9 cells with important clinical implications ((a) Zhao, Y.; Chu, X.; Chen, J.; Wang, Y.; Gao, S.; Jiang, Y.; Zhu, X.; Tan, G.; Zhao, W.; Yi, H.; Xu, H.; Ma, X.; Lu, Y.; Yi, Q.; Wang, S. Dectin-1 - activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells. Nat. Commun.
- the effect of its activation is evident in the up-regulation of co stimulatory molecules such as CD80, and in the production of TNF-a, IL-6, IL-2, IL- 10, IL-12 and IL-23, and in determining cytotoxic T cell (CTL) responses
- the main object of the present invention is therefore the identification of a new type of Dectin-1 ligands that can be used for the prevention and treatment of fungal diseases, widespread inflammatory diseases related to pathogenic infections and autoimmune responses, in the treatment of tumors, as well as adjuvants for vaccines.
- the present invention refers to a compound of formula (I):
- R 1 is selected from the group consisting of: CH(CH 3 )CH 2 CH 2 R 2 and CH(CH 3 )CHCHCHR 3 CHR 4 CH 3 , R 2 being CH 2 CH(CH 3 ) 2 , R 3 being selected from H and CH 3 , and CH 2 CH 3 , and R 4 being selected from CH 3 and CH(CH 3 ) 2 ;
- R 5 is selected from the group consisting of: OC(O)R 6 , OSO 3 H, SO 3 H, OPO 3 H 2 , OPO 3 (CH 3 ) 2 , PO 3 H 2 ; monosaccharyl, R 6 being a C 1 -C 20 alkyl group;
- a and B independently represent a single bond or a double bond; or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a fungal disease, an inflammatory disease, a tumor disease, or for use as an adjuvant for a vaccine.
- the inventors have in fact surprisingly discovered that the sterol derivatives according to the general formula (I) and pharmaceutically acceptable salts thereof can be used as Dectin-1 ligands, thus allowing the use thereof for the prevention and treatment of fungal, inflammatory and tumor diseases, as well as adjuvants for vaccines.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound according to the first aspect of the present invention, and a pharmaceutically acceptable carrier.
- the present invention further relates to a compound according to the first aspect of the invention, for use as a Dectin-1 receptor ligand or as an immunostimulating substance in the treatment of a disease related to Dectin-1 receptor.
- said receptor plays a key role in the immune response to various types of diseases; the compounds according to the first aspect of the invention, by performing the function of ligands of said receptor, favor the activation of the immune response counteracting said diseases.
- Figure 4 shows the results of the surface phenotypes maturation test on moDCs dendritic cells carried out with monosulfate cholesterol [Phenotypic analysis relating to the expression of surface markers for the maturation of moDCs and cell viability after stimulation with cholesterol sulfate in the 0.01-100 ⁇ g/mL range. Data are expressed as mean fluorescence intensity (MFI) and as viability %];
- Figure 5 shows the results of the surface phenotypes maturation test on D1 cells carried out with monosulfate cholesterol [Phenotypic analysis relating to the expression of surface markers for the maturation of D1 cells and cell viability after stimulation with cholesterol sulfate in the 0.01-100 ⁇ g/mL range. Data are expressed as mean fluorescence intensity (MFI) and as viability %];
- Figure 6 shows the results of the 6-hour Real Time analysis of gene expression assays on interleukin-moDCs performed with monosulfate cholesterol [Analysis of gene expression for cytokines in moDCs, carried out by Real Time analysis after 6h of stimulation with CHOS at concentrations of 1-10-30 ⁇ g/mL]; and Figure 7 shows the results of the 24-hour Real Time analysis of gene expression assays on interleukin-moDCs performed with monosulfate cholesterol [Analysis of gene expression for cytokines in moDCs, carried out by Real Time analysis after 24h of stimulation with CHOS at concentrations of 1-10-30 ⁇ g/mL],
- the present invention refers to a compound of formula (I):
- R 1 is selected from the group consisting of: CH(CH 3 )CH 2 CH 2 R 2 and CH(CH 3 )CHCHCHR 3 CHR 4 CH 3 , R 2 being CH 2 CH(CH 3 ) 2 , R 3 being selected from H and CH 3 , and CH 2 CH 3 , and R 4 being selected from CH 3 and CH(CH 3 ) 2 ;
- R 5 is selected from the group consisting of: OC(O)R 6 , OSO 3 H, SO 3 H, OPO 3 H 2 , OPO 3 (CH 3 ) 2 , PO 3 H 2 ; monosaccharyl, R 6 being a C 1 -C 20 alkyl group;
- a and B independently represent a single bond or a double bond; or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a fungal disease, an inflammatory disease, a tumor disease, or for use as an adjuvant for a vaccine.
- the inventors have in fact surprisingly discovered that the sterol derivatives according to the general formula (I) and pharmaceutically acceptable salts thereof can be used as ligands of Dectin-1 , thus allowing the use thereof for the prevention and treatment of fungal, inflammatory and tumor diseases, as well as adjuvants for vaccines.
- the present invention may have in one or more aspects thereof one or more of the preferred characteristics reported hereinafter, which can be combined with each other according to the application requirements.
- the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and treatment of fungal diseases, inflammatory diseases, and tumor diseases, as well as for the use as adjuvants for vaccines.
- a pharmaceutically acceptable salt of the compound of formula (I) include a salt of a monovalent cation, such as sodium or potassium ion.
- R 1 is CH(CH 3 )CH 2 CH 2 R 2 and R 2 is CH 2 CH(CH 3 ) 2 .
- the monosaccharyl of the group R 5 is preferably selected from the group consisting of: glucosyl, sulfoquinovosyl, and derivatives thereof. More preferably, preferably the monosaccharyl of the group R 5 is selected from the group consisting of glucosyl, sulfoquinovosyl, peracetylated glucosyl, peracetylated sulfoquinovosyl.
- R 5 is selected from the group consisting of OSO 3 H, SO 3 H, OPO 3 H 2 , OPO 3 (CH 3 ) 2 , PO 3 H 2 ; more preferably, R 5 is selected from the group consisting of OSO 3 H, OPO 3 H 2 , and OPO 3 (CH 3 ) 2 ; even more preferably R 5 is OSO 3 H.
- A represents a double bond
- B represents a single bond
- the compound according to the present invention is selected from the group consisting of: - stigmasterol sulfate
- the compound according to the present invention is cholesterol sulfate: or a pharmaceutically acceptable salt thereof.
- the compound according to the present invention may be prepared according to any of the synthetic strategies known for the purpose in the literature for preparing sterol derivatives.
- sulfate cholesterol may be advantageously prepared by sulfatation of a natural sterol, as described for example in the literature (C. Gallo, G. Nuzzo, G. D’lppolito, E. Manzo, A. Sardo, A. Fontana.
- the compound according to the present invention has proved effective as a Dectin- 1 receptor ligand; this allows to use said compound for the prevention and treatment of fungal, inflammatory and tumor diseases, as well as adjuvants for vaccines.
- the compound according to the present invention is used for the prevention and treatment of a human subject.
- said fungal disease is selected from the group consisting of mycoses such as candidiasis, aspergillosis, mucormycosis, fusariosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, cryptococcosis, penicillosis, and pneumocytosis.
- mycoses such as candidiasis, aspergillosis, mucormycosis, fusariosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, cryptococcosis, penicillosis, and pneumocytosis.
- said inflammatory disease is a diffuse inflammatory disease related to a pathogen infection or to an autoimmune response preferably selected from the group consisting of arthritis, colitis, allergy, sepsis, septic shock, and an autoimmune disease.
- said tumor is selected from the group consisting of carcinoma, sarcoma, melanoma, and myeloma.
- the present invention refers to a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound according to the first aspect of the present invention, and at least one pharmaceutically acceptable carrier.
- the compounds according to the first aspect of the invention and the pharmaceutical compositions that contain them find particular application in the treatment of humans.
- the pharmaceutical composition according to the present invention includes any composition produced by mixing at least one compound according to the first aspect of the invention and at least one pharmaceutically acceptable carrier. This type of compositions are suitable for pharmaceutical use in an animal or in humans.
- the pharmaceutical composition according to the present invention includes a therapeutically effective amount of one or more compounds according to the first aspect of the invention and at least one pharmaceutically acceptable carrier.
- composition according to the present invention may be conveniently presented in a single-dose form and prepared with any of the methods well known in the pharmaceutical art.
- composition according to the present invention may optionally contain other active ingredients.
- carrier means any excipient, or diluent, with which a compound according to the present invention is administered.
- any carrier or excipient suitable for the form of preparation desired for adm inistration is contemplated for use with the compound according to the present invention.
- the carrier may have a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous).
- any of the usual pharmaceutical media may be used such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes, and the like, in the case of oral liquid preparations such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of solid oral preparations such as, for example, powders, hard and soft capsules, and tablets, with the solid oral preparations being preferred compared to liquid preparations.
- oral liquid preparations such as, for example, suspensions, elixirs and solutions
- carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like
- solid oral preparations such as, for example, powders, hard and soft capsules, and tablets, with the solid oral preparations being preferred
- the compound according to the present invention may also be used in combination with another compound having the same or different activity to prepare a pharmaceutical composition.
- the compounds according to the present invention may be combined in a mixture with a suitable pharmaceutical carrier in accordance with conventional pharmaceutical compound manufacturing techniques.
- composition according to the present invention is advantageously suitable for parenteral administration including subcutaneous, intramuscular, and intravenous, pulmonary, nasal, rectal, topical, or oral administration.
- an exemplary route of administration is the parenteral route.
- the pharmaceutical composition according to the present invention may be administered by the intramuscular, intravenous, intracutaneous, or subcutaneous route.
- a pharmaceutical composition or preparation to be administered parenterally may be formulated by dissolving, suspending, or emulsifying any compound or mixtures thereof, in a suitable aqueous or fat-based solvent such as, for example, a vegetable oil, a glyceride with a fatty acid, an ester of a higher fatty acid using commonly used pharmaceutical techniques.
- the pharmaceutical composition for parenteral use may contain at least one excipient or carrier such as, for example, a solubilizing agent, a suspending agent, an emulsifier, a stabilizer, and a preservative.
- compositions and preparations may contain at least 0.1% of the compound of formula (I).
- the percentage of said compound of formula (I) in these compositions may, of course, be varied and conveniently can be between about 1% and about 60% of the weight of the unit.
- the amount of compound in these compositions useful from a prophylactic or therapeutically point of view is such that an effective dosage, from a therapeutically or prophylactic point of view, will be obtained.
- the administration of the pharmaceutical composition according to the present invention is carried out following a protocol and at a dosage sufficient to determine the therapeutic response in the treated subject.
- the compound in the pharmaceutical compositions of the present invention, is formulated in dosage units.
- the dosage unit may contain from 0.1 to 1000 mg of a compound of formula (I) and per dosage unit for daily administration.
- the effective amounts for the formulation will depend on the severity of the disease, disorder, or condition, on the previous therapy, on the subject’s state of health, and on the response to the drug.
- the dose belongs to the range from 0.001% by weight to about 60% by weight of the formulation.
- the other active ingredients may be used in lower doses than when each one is used individually.
- the formulations relating to any variety of administration routes the methods and formulations for administering drugs are known to those skilled in the art, for example from what is reported in Remington’s Pharmaceutical Sciences, XVII Edizione, Gennaro et at. Ed., Mack Publishing Co., 1985, and Remington’s Pharmaceutical Sciences, Gennaro AR ed.
- the dosage of administration of the compound according to the present invention varies according to the form and route of administration and the type of disease to be treated.
- the daily dosage of the compound of formula (I) may vary from 1 to 100 mg/kg of body weight.
- the present invention further relates to the compound according to the first aspect of the invention for use as a Dectin-1 receptor ligand or as an immunostimulating substance in a disease related to the Dectin-1 receptor.
- said receptor plays a key role in the immune response to various types of diseases; the compounds according to the first aspect of the invention by performing the function of ligands of said receptor favor the activation of the immune response against said diseases.
- Example 2 Activity assays for cholesterol sulfate according to Examplel
- the cholesterol sulfate according to Example 1 was tested in a binding assay on Dectin-1 reporter cells to evaluate a possible receptor interaction.
- the data for Dectin-1 activation were then compared with the values of the standard Zymosan, a Dectin-1 ligand.
- the assays showed a more efficient receptor binding for cholesterol sulfate as compared to Zymosan ( Figure 1).
- cholesterol sulfate induced the maturation of moDC and D1 dendritic cells, as evident from the expression of typical surface phenotypic markers ( Figures 2-3).
- cholesterol sulfate according to Example 1 is suitable to play the role of Dectin-1 receptor ligand, thus allowing a use of the compound according to the present invention for the prevention and treatment of fungal, inflammatory, and tumor diseases.
- Example 4 Binding assays on Dectin-1 reporter cells for cholestanol sulfate according to Example 3
- the cholestanol sulfate according to Example 3 was tested in a binding assay on Dectin-1 reporter cells to evaluate a possible receptor interaction. The data for Dectin-1 activation were then compared with the values of the standard Zymosan, a Dectin-1 ligand. The tests showed a binding to the receptor for cholestanol sulfate ( Figure 2). Based on this evidence, it was therefore possible to conclude that cholestanol sulfate according to Example 3 is suitable to play the role of Dectin-1 receptor ligand, thus allowing a use of the compound according to the present invention for the prevention and treatment of fungal, inflammatory, and tumor diseases.
- Example 5 Synthesis of ⁇ -sulfoquinovosyl-cholesterol ⁇ -Sulfoquinovosyl-cholesterol was synthesized following the procedure inspired by Manzo et al. and Ziaco et a/.
- Example 6 Binding assays on Dectin-1 reporter cells for ⁇ -sulfoquinovosyl- cholesterol according to Example 5
- the ⁇ -sulfoquinovosyl-cholesterol according to Example 5 was tested in a binding assay on Dectin-1 reporter cells to evaluate a possible receptor interaction.
- the data for Dectin-1 activation were then compared with the values of the standard Zymosan, a Dectin-1 ligand.
- the tests showed a binding to the receptor for ⁇ - sulfoquinovosyl-cholesterol ( Figure 3). Based on this evidence, it was therefore possible to conclude that ⁇ -sulfoquinovosyl-cholesterol according to Example 5 is suitable to play the role of Dectin-1 receptor ligand, thus allowing a use of the compound according to the present invention for the prevention and treatment of fungal, inflammatory, and tumor diseases.
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Abstract
The present invention relates in particular to the use of sterol derivatives as Dectin-1 receptor ligands in the prevention and treatment of diseases related to said receptor. The invention also refers to compositions and uses of such sterol derivatives as immunostimulants for the prevention and treatment of fungal diseases, widespread inflammatory diseases related to pathogenic infections and autoimmune responses, as well as tumors.
Description
STEROL DERIVATIVES AS NEW DECTIN-1 RECEPTOR LIGANDS IN THE THERAPEUTIC TREATMENT OF DISEASES RELATED TO SAID RECEPTOR
DESCRIPTION FIELD OF THE INVENTION
The present invention originates in the pharmaceutical field and relates in particular to the use of sterol derivatives as Dectin-1 receptor ligands in the prevention and treatment of diseases related to said receptor. The invention also refers to compositions and uses of such sterol derivatives as immunostimulants for the prevention and treatment of fungal diseases, widespread inflammatory diseases related to pathogenic infections and autoimmune responses, as well as tumors.
STATE OF THE ART
The immune system recognizes and responds to pathogens through the so-called ‘antigen presenting cells’ (APC), which play a fundamental role in controlling the interface of innate and acquired immunity by activating the cascade of intra- and inter-cellular signals. This recognition depends on the expression of specialized surface receptors, the ‘pattern recognition receptors’ (PRRs) (Kawai, T.; Akira, S. The roles of TLRs, RLRs and NLRs in pathogen recognition. International Immunology 2009, 21 (4), 317-337), mainly represented by toll-like (TLR) receptors, C-type-lectin (CLR), NOD-like (NLR) and RIG-l-like (RLR) receptors, which are able to recognize pathogen-associated molecular patterns (PAMP) and different cell damage-associated molecular patterns (DAMP). The recognition of PAMPs and DAMPs leads to activation of the antimicrobial and inflammatory response by APCs, including macrophages and dendritic cells (DCs), and to activation of the adaptive immune response for eliminating the pathogen (Palm, N.W; Medzhitov, R. Pattern recognition receptors and control of adaptive immunity. Immunological Reviews, 2009, 227, 221-233).
PRRs are therefore therapeutic targets as they can be ‘exploited’ by their natural and/or artificial ligands, in order to activate the immune defenses and modulate them in order to provide adequate protection to the body.
Immune cell receptors ligands may consequently have great clinical potential for the development of therapies aimed at the resolution of various diseases.
CLRs, after TLRs, represent the second most important class of PRRs capable of activating APCs and developing a robust Th1 and Th17 response that makes these receptors potential targets of anti-infectious vaccines adjuvants and capable of orchestrating adequate and balanced immunogenic response. In fact, there is evidence of the ability of some CLRs to interact (cross-talk) with other families of PRR receptors such as TLRs, by amplifying and/or down-regulating their inflammatory responses, thus highlighting the ability to modulate the immunogenic response in such a way that this is effective, by favoring a ‘fine tuning’ necessary to avoid harmful and/or autoimmune reactions (Brown, G.D.; Willment, J.A.; Whitehead, L. C-type lectins in immunity and homeostasis. Nat. Rev. Immunol. 2018, 18(6), 374-389).
CLRs’ functions are therefore essential for cellular immunity and homeostasis. This family of receptors consists of over 1000 proteins divided into 17 groups based on their structure and/or function.
Dectin-1 (CLEC-7A) is one of the most studied and characterized CLR receptors and is mainly expressed on myeloid cells, including monocytes, macrophages, DCs, and neutrophils ((a) Brown, G.D.; Crocker, P.R. Lectin Receptors Expressed on Myeloid Cells. Microbiol. Spectr. 2016, 4(5), doi: 10.1128/microbiolspecMCHD- 0036-2016;
(b) Sun, W.K.; Lu, X.; Li, X.; Sun, Q.Y.; Su, X.; Song, Y.; Sun H.M.; Shi Y. Dectin-1 is inducible and plays a crucial role in Aspergillus-induced innate immune responses in human bronchial epithelial cells. Eur. J. Clin. Microbiol. Infect. Dis. 2012, 31(10), 2755-64). Dectin-1 is also expressed on B cells and on some subsets of T cells as well as on epithelial cells ((a) Brown, G.D.; Crocker, P.R. Lectin Receptors Expressed on Myeloid Cells. Microbiol. Spectr. 2016, 4(5), doi:
10.1128/m icrobiolspec.MCHD-0036-2016; (b) Ariizumi, K.; Shen, G.L.; Shikano, S.; Xu, S.; Ritter, R.; Kumamoto, T.; Edelbaum, D.; Morita, A.; Bergstresser, P.R.; Takashima, A. Identification of a novel, dendritic cell-associated molecule, dectin-1 , by subtractive cDNA cloning. J. Biol. Chem. 2000, 275(26), 20157-67). This receptor is best known for its ability to bind β-1 ,3 glucans. These carbohydrates are
commonly found on fungi cell walls, and as a result, Dectin-1 plays a key role in anti fungal immunity, as it recognizes numerous fungal species including pathogens such as Candida albicans, Aspergillus fumigatus, Coccidioides immitis and Pneumocystis carinii ((a)Hardison, S.E.; Brown, G.D. C-type lectin receptors orchestrate antifungal immunity. Nat. Immunol. 2012, 13(9), 817-22; (b) Viriyakosol, S.; Jimenez, M.P.; Gurney, M.A.; Ashbaugh, M.E.; Fierer, J. Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice. Mbio. Asm Org. 2013, 4(1), e00597- 12). Gene variations of human Dectin-1 can also translate into increased susceptibility to infections with A. fumigatus, Trichophyton rubrum and C. albicans ((a) Ferwerda, B.; Ferwerda, G.; Plantinga, T.S.; Willment, J.A.; Van Spriel, A.B.; Venselaar, H.; Elbers, C.C.; Johnson, M.D.; Cambi, A.; Huysamen, C.; Jacobs, L; Jansen, T.; Verheijen, K.; Masthoff, L.; Morre, S.A.; Vriend, G.; Williams, D.L.; Perfect, J.R.; Joosten, L.A.; Wijmenga, C.; Van der Meer, J.W.; Adema, G.J.; Kullberg, B.J.; Brown, G.D.; Netea, M.G. Human dectin-1 deficiency and mucocutaneous fungal infections. N. Engl. J. Med. 2009, 361(18), 1760-1767; (b) Cunha, C.; Di lanni, M.; Bozza, S.; Giovannini, G.; Zagarella, S.; Zelante, T.; D’Angelo, C.; Pierini, A.; Pitzurra, L.; Falzetti, F.; Carotti, A.; Perruccio, K.; Latge, J.P.; Rodrigues, F.; Velardi, A.; Aversa, F.; Romani, L.; Carvalho, A. Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor- dependent mechanisms of antifungal immunity. Blood 2010, 116(24), 5394-5402). Ligand recognition by Dectin-1 can trigger and regulate numerous cellular responses, including phagocytosis, autophagy, DC maturation, and cytokine and chemokine production. In addition to its role in anti-fungal immunity, there is evidence that Dectin-1 plays a much larger role in immunity, with the ability to recognize other types of pathogens including Haemophilus influenzae, Salmonella typhimurium, Mycobacterium tuberculosis and Leishmania infantum ((a) Drummond, R.A.; Brown, G.D. Signalling C-Type Lectins in Antimicrobial Immunity. PLoS Pathog. 2013, 9(7), e1003417; (b) Lefevre, L.; Lugo-Villarino, G.; Meunier, E.; Valentin, A.; Olagnier, D.; Authier, H.; Duval, C.; Dardenne, C.; Bernad, J.; Lemesre, J.L.; Auwerx, J.; Neyrolles, O.; Pipy, B.; Coste, A. The C-type lectin receptors dectin-1 , MR, and SIGNR3 contribute both
positively and negatively to the macrophage response to Leishmania infantum. Immunity 2013, 38(5), 1038-1049).
Dectin-1 is able to determine the development of adaptive immune responses by differentiating Th1 and Th17 responses ((a) Drummond, R.A; Brown, G.D. The role of Dectin-1 in the host defence against fungal infections. Curr. Opin. Microbiol. 2011, 14(4), 392-9; (b) LeibundGut-Landmann, S.; Gross, O.; Robinson, M.J,.; Osorio, F.; Slack, E.C.; Tsoni, S.V.; Schweighoffer, E.; Tybulewicz, V.; Brown, G.D.; Ruland, J.; Reis e Sousa, C. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat. Immunol. 2007, 8(6), 630-638; Hardison, S.E.; Brown, G.D. C-type lectin receptors orchestrate antifungal immunity. Nat. Immunol. 2012, 13(9), 817-22; (c) Kashem, S.W.; Igyarto, B.Z.; Gerami-Nejad, M.; Kumamoto, Y.; Mohammed, J.A.; Jarrett, E.; Drummond, R.A.; Zurawski, S.M.; Zurawski, G.; Berman, J.; Iwasaki, A.; Brown, G.D.; Kaplan, D.H. Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation. Immunity 2015, 42(2), 356-366). While Th1 responses are important for the control of systemic fungal infections, Th17 responses are critical for the control of mucosal fungal infections.
This receptor also promotes humoral responses via Th2 (Kaisar, M.; Ritter, M.; Del Fresno, C.; Jonasdottir, H.S.; Van der Ham, A.J.; Pelgrom, L.R.; Schramm, G.; Layland, L.E.; Sancho, D.; Da Costa, C.P.; Giera, M.; Yazdanbakhsh, M.; Everts B. Dectin-1 /2-induced autocrine PGE2 signaling licenses dendritic cells to prime Th2 responses. Plos Biology 2018, doi.org/10.1371/journal.pbio.2005504) and, through the regulation of IL-22 and IL-33, it is crucial in the regulation of allergic diseases ((a) Gour, N.; Lajoie, S.; Smole, U.; White, M.; Hu, D.; Goddard, P.; Huntsman, S.; Eng, C.; Mak, A.; Oh, S.; Kim, J.H.; Sharma, A.; Plante, S.; Salem, I.H.; Resch, Y.; Xiao, X.; Yao, N.; Singh, A.; Vrtala, S.; Chakir, J.; Burchard, E.G.; Lane, A.P.; Wills- Karp, M. Dysregulated invertebrate tropomyosin-dectin-1 interaction confers susceptibility to allergic diseases. Sci. Immunol. 2018, 3(20), eaam9841; (b) Ito, T.; Hirose, K.; Norimoto, A.; Tamachi, T.; Yokota, M.; Saku, A.; Takatori, H.; Saijo, S.; Iwakura, Y.; Nakajima, H. Dectin-1 Plays an Important Role in House Dust Mite- Induced Allergic Airway Inflammation through the Activation of CD11 b+ Dendritic Cells. J. Immunol. 2017, 198(1 ), 61-70).
Dectin-1 is also implicated in allergies and in the regulation of autoimmune diseases, such as arthritis and colitis (Yoshitomi, H.; Sakaguchi, N.; Kobayashi, K.; Brown, G.D.; Tagami, T.; Sakihama, T.; Hirota, K.; Tanaka, S.; Nomura, T.; Miki, I.; Gordon, S.; Akira, S.; Nakamura, T.; Sakaguchi, S. A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J. Exp. Med. 2005, 201(6), 949-960) thanks to the ability to control the excessive inflammation induced by pathogenic fungi during ulcerative colitis. Another important function linked to this receptor is in fact the ability to mediate and modulate inflammatory responses determined by TLR4 with which not only it can cooperate by amplifying the production of pro-inflammatory cytokines against fungi and bacteria, but it can also determine a suppression of inflammatory cytokines with production of anti-inflammatory proteins (IL 10), thus favoring the achievement of homeostatic conditions. Furthermore, Dectin-1 expression is up-regulated in hepatic fibrosis and liver cancer, and the lack of this receptor causes a worsening of liver fibro-inflammatory disease, accelerating its hepatocarcinogenesis. Dectin-1 therefore protects against chronic liver diseases by suppressing TLR4 action, mitigating the expression of this receptor and the corresponding CD14 co-receptor. More generally, this cross-talk implies a role for Dectin-1 in the suppression of sterile inflammation, inflammation-induced oncogenesis, and LPS-mediated sepsis (Seifert, L; Deutsch, M.; Alothman, S.; Alqunaibit, D.; Werba, G.; Pansari, M.; Pergamo, M.; Ochi, A.; Torres-Flernandez, A.; Levie, E.; Tippens, D.; Greco, S.H.; Tiwari, S.; Ly, N.N.G.; Eisenthal, A.; Van Fleerden, E.; Avanzi, A.; Barilla, R.; Zambirinis, C.P.; Rendon, M.; Daley, D.; Pachter, H.L.; Hajdu, C.; Miller, G. Dectin- 1 Regulates Flepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways. Cell Rep. 2015, 13(9), 1909-1921).
Dectin-1 also plays an important role in the field of anti-tumor immunity as demonstrated by its ability to promote the differentiation of Th9 cells with important clinical implications ((a) Zhao, Y.; Chu, X.; Chen, J.; Wang, Y.; Gao, S.; Jiang, Y.; Zhu, X.; Tan, G.; Zhao, W.; Yi, H.; Xu, H.; Ma, X.; Lu, Y.; Yi, Q.; Wang, S. Dectin-1 - activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells. Nat. Commun. 2016, 7, doi: 10.1038/ncomms12368; (b) Chen, J.; Zhao, Y.; Chu, X.; Lu, Y.; Wang, S.; Yi, Q. Dectin-1 -activated dendritic cells: A potent Th9
cell inducer for tumor immunotherapy. Oncoimmunology 2016, 5 (11), e1238558 (3 pages)).
In this regard, the effect of its activation is evident in the up-regulation of co stimulatory molecules such as CD80, and in the production of TNF-a, IL-6, IL-2, IL- 10, IL-12 and IL-23, and in determining cytotoxic T cell (CTL) responses
(LeibundGut-Landmann, S.; Osorio, F.; Brown, G.D.; Reis e Sousa, C. Stimulation of dendritic cells via the dectin-1/Syk pathway allows priming of cytotoxic T-cell responses. Blood 2008, 112 (13), 4971-4980). Furthermore, molecular structures of N-glycans, present on the surface of tumor cells, are recognized by Dectin-1 , thus confirming its role in anti-tumor immunity (Chiba, S.; Ikushima, FI.; Ueki, H.; Yanai, FI.; Kimura, Y.; Flangai, S.; Nishio, J.; Negishi, H.; Tamura, T.; Saijo, S.; Iwakura, Y.; Taniguchi, T. Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses. Elite 2014, 3:e04177). In addition, activation by β- glucan ligands determines the increase in activated T cells infiltration within the tumor.
All this highlights the enormous importance linked to the research and development of new Dectin-1 ligands, and the pharmacological and therapeutic potential underlying this research.
The identification and characterization of these ligands are in fact able to open to the development of new therapeutic strategies for the prevention and treatment of fungal diseases, widespread inflammatory diseases related to pathogenic infections and autoimmune responses, as well as in the treatment of tumors.
The main object of the present invention is therefore the identification of a new type of Dectin-1 ligands that can be used for the prevention and treatment of fungal diseases, widespread inflammatory diseases related to pathogenic infections and autoimmune responses, in the treatment of tumors, as well as adjuvants for vaccines.
SUMMARY OF THE INVENTION In a first aspect, therefore, the present invention refers to a compound of formula (I):
wherein: R1 is selected from the group consisting of: CH(CH3)CH2CH2R2 and CH(CH3)CHCHCHR3CHR4CH3, R2 being CH2CH(CH3)2, R3 being selected from H and CH3, and CH2CH3, and R4 being selected from CH3 and CH(CH3)2; R5 is selected from the group consisting of: OC(O)R6, OSO3H, SO3H, OPO3H2, OPO3(CH3)2, PO3H2; monosaccharyl, R6 being a C1-C20 alkyl group;
A and B independently represent a single bond or a double bond; or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a fungal disease, an inflammatory disease, a tumor disease, or for use as an adjuvant for a vaccine.
The inventors have in fact surprisingly discovered that the sterol derivatives according to the general formula (I) and pharmaceutically acceptable salts thereof can be used as Dectin-1 ligands, thus allowing the use thereof for the prevention and treatment of fungal, inflammatory and tumor diseases, as well as adjuvants for vaccines.
In a further aspect thereof, the present invention also relates to a pharmaceutical composition comprising at least one compound according to the first aspect of the present invention, and a pharmaceutically acceptable carrier. The advantages of the pharmaceutical composition according to the present invention were already outlined with reference to the compound according to the first aspect of the invention and are not repeated here.
In a further aspect, the present invention further relates to a compound according to the first aspect of the invention, for use as a Dectin-1 receptor ligand or as an
immunostimulating substance in the treatment of a disease related to Dectin-1 receptor.
In fact, said receptor plays a key role in the immune response to various types of diseases; the compounds according to the first aspect of the invention, by performing the function of ligands of said receptor, favor the activation of the immune response counteracting said diseases.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the results of the binding assay on Dectin-1 reporter cells carried out with cholesterol monosulfate, and the comparison with the values of the standard zymosan, a Dectin-1 ligand [Zymosan = 100 ug/mL; CHOS (0.001-100 ug/mL) n=3 (3 biological replicates; 3 technical replicates for each n)];
Figure 2 shows the results of the binding assay on Dectin-1 reporter cells carried out with cholestanol monosulfate, and the comparison with the values of the standard zymosan, a Dectin-1 ligand [Zymosan = 100 ug/mL; Cholestanol sulfate (0.001-60 ug/mL) n=3 (3 biological replicates; 3 technical replicates for each n)];
Figure 3 shows the results of the binding assay on Dectin-1 reporter cells carried out with β-sulfoquinovosyl-cholesterol, and the comparison with the values of the standard zymosan, a Dectin-1 ligand [Zymosan = 100 ug/mL; Sulfoquinovosyl cholesterol (0.001-60 ug/mL) n=3 (3 biological replicates; 3 technical replicates for each n)];
Figure 4 shows the results of the surface phenotypes maturation test on moDCs dendritic cells carried out with monosulfate cholesterol [Phenotypic analysis relating to the expression of surface markers for the maturation of moDCs and cell viability after stimulation with cholesterol sulfate in the 0.01-100 μg/mL range. Data are expressed as mean fluorescence intensity (MFI) and as viability %];
Figure 5 shows the results of the surface phenotypes maturation test on D1 cells carried out with monosulfate cholesterol [Phenotypic analysis relating to the expression of surface markers for the maturation of D1 cells and cell viability after stimulation with cholesterol sulfate in the 0.01-100 μg/mL range. Data are expressed as mean fluorescence intensity (MFI) and as viability %];
Figure 6 shows the results of the 6-hour Real Time analysis of gene expression
assays on interleukin-moDCs performed with monosulfate cholesterol [Analysis of gene expression for cytokines in moDCs, carried out by Real Time analysis after 6h of stimulation with CHOS at concentrations of 1-10-30 μg/mL]; and Figure 7 shows the results of the 24-hour Real Time analysis of gene expression assays on interleukin-moDCs performed with monosulfate cholesterol [Analysis of gene expression for cytokines in moDCs, carried out by Real Time analysis after 24h of stimulation with CHOS at concentrations of 1-10-30 μg/mL],
DETAILED DESCRIPTION OF THE INVENTION In a first aspect, the present invention refers to a compound of formula (I):
(I)
B wherein: R1 is selected from the group consisting of: CH(CH3)CH2CH2R2 and CH(CH3)CHCHCHR3CHR4CH3, R2 being CH2CH(CH3)2, R3 being selected from H and CH3, and CH2CH3, and R4 being selected from CH3 and CH(CH3)2;
R5 is selected from the group consisting of: OC(O)R6, OSO3H, SO3H, OPO3H2, OPO3(CH3)2, PO3H2; monosaccharyl, R6 being a C1-C20 alkyl group;
A and B independently represent a single bond or a double bond; or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a fungal disease, an inflammatory disease, a tumor disease, or for use as an adjuvant for a vaccine.
The inventors have in fact surprisingly discovered that the sterol derivatives according to the general formula (I) and pharmaceutically acceptable salts thereof can be used as ligands of Dectin-1 , thus allowing the use thereof for the prevention and treatment of fungal, inflammatory and tumor diseases, as well as adjuvants for
vaccines.
Within the scope of the present description, and in the subsequent claims, all numerical quantities indicating amounts, parameters, percentages, and so on are to be intended in all circumstances as preceded by the term “about”, unless otherwise indicated. Furthermore, all numerical quantities ranges include all possible combinations of the maximum and minimum numerical values and all possible intermediate ranges, in addition to those specifically indicated below.
The present invention may have in one or more aspects thereof one or more of the preferred characteristics reported hereinafter, which can be combined with each other according to the application requirements.
In a first aspect thereof, the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and treatment of fungal diseases, inflammatory diseases, and tumor diseases, as well as for the use as adjuvants for vaccines. Examples of a pharmaceutically acceptable salt of the compound of formula (I) include a salt of a monovalent cation, such as sodium or potassium ion.
Preferably, in the compound of formula (I) R1 is CH(CH3)CH2CH2R2 and R2 is CH2CH(CH3)2.
In the compound of formula (I) the monosaccharyl of the group R5 is preferably selected from the group consisting of: glucosyl, sulfoquinovosyl, and derivatives thereof. More preferably, preferably the monosaccharyl of the group R5 is selected from the group consisting of glucosyl, sulfoquinovosyl, peracetylated glucosyl, peracetylated sulfoquinovosyl.
Preferably, in the compound of formula (I) R5 is selected from the group consisting of OSO3H, SO3H, OPO3H2, OPO3(CH3)2, PO3H2; more preferably, R5 is selected from the group consisting of OSO3H, OPO3H2, and OPO3(CH3)2; even more preferably R5 is OSO3H.
Preferably, in the compound of formula (I) A represents a double bond, and B represents a single bond. In a preferred embodiment, the compound according to the present invention is selected from the group consisting of:
- stigmasterol sulfate
- ergosterol sulfate:
- β-sulfoquinovosyl-cholesterol:
- cholestanol sulfate:
- cholesterol sulfate:
or a pharmaceutically acceptable salt thereof.
In a particularly preferred and advantageous embodiment, the compound according to the present invention is cholesterol sulfate:
or a pharmaceutically acceptable salt thereof. The compound according to the present invention may be prepared according to any of the synthetic strategies known for the purpose in the literature for preparing sterol derivatives. For example, sulfate cholesterol may be advantageously prepared by sulfatation of a natural sterol, as described for example in the literature (C. Gallo, G. Nuzzo, G. D’lppolito, E. Manzo, A. Sardo, A. Fontana. “Chapter Five - Sterol Sulfates and Sulfotransferases in Marine Diatoms", from Methods in Enzymology (Marine Enzymes and Specialized Metabolism - Part B), 2018, vol. 605, pp. 101-13; ISBN: 9780128150450).
The compound according to the present invention has proved effective as a Dectin- 1 receptor ligand; this allows to use said compound for the prevention and treatment of fungal, inflammatory and tumor diseases, as well as adjuvants for vaccines.
Preferably, the compound according to the present invention is used for the prevention and treatment of a human subject.
Preferably, said fungal disease is selected from the group consisting of mycoses such as candidiasis, aspergillosis, mucormycosis, fusariosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, cryptococcosis, penicillosis, and pneumocytosis.
Preferably, said inflammatory disease is a diffuse inflammatory disease related to a pathogen infection or to an autoimmune response preferably selected from the group consisting of arthritis, colitis, allergy, sepsis, septic shock, and an autoimmune disease.
Preferably, said tumor is selected from the group consisting of carcinoma, sarcoma,
melanoma, and myeloma.
In a further aspect thereof, the present invention refers to a pharmaceutical composition comprising at least one compound according to the first aspect of the present invention, and at least one pharmaceutically acceptable carrier. The advantages of the pharmaceutical composition according to the present invention were already outlined with reference to the compound according to the first aspect of the invention and are not repeated here.
The compounds according to the first aspect of the invention and the pharmaceutical compositions that contain them find particular application in the treatment of humans.
The pharmaceutical composition according to the present invention includes any composition produced by mixing at least one compound according to the first aspect of the invention and at least one pharmaceutically acceptable carrier. This type of compositions are suitable for pharmaceutical use in an animal or in humans. The pharmaceutical composition according to the present invention includes a therapeutically effective amount of one or more compounds according to the first aspect of the invention and at least one pharmaceutically acceptable carrier.
The pharmaceutical composition according to the present invention may be conveniently presented in a single-dose form and prepared with any of the methods well known in the pharmaceutical art.
The pharmaceutical composition according to the present invention may optionally contain other active ingredients.
For the purposes of the present application, the term “carrier” means any excipient, or diluent, with which a compound according to the present invention is administered.
Any carrier or excipient suitable for the form of preparation desired for adm inistration is contemplated for use with the compound according to the present invention. The carrier may have a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous). In preparing the compositions for the oral dosage form, any of the usual pharmaceutical media may be used such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes, and the like, in the case of oral liquid
preparations such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of solid oral preparations such as, for example, powders, hard and soft capsules, and tablets, with the solid oral preparations being preferred compared to liquid preparations.
In some embodiments the compound according to the present invention may also be used in combination with another compound having the same or different activity to prepare a pharmaceutical composition.
In certain embodiments, the compounds according to the present invention may be combined in a mixture with a suitable pharmaceutical carrier in accordance with conventional pharmaceutical compound manufacturing techniques.
The pharmaceutical composition according to the present invention is advantageously suitable for parenteral administration including subcutaneous, intramuscular, and intravenous, pulmonary, nasal, rectal, topical, or oral administration.
An exemplary route of administration is the parenteral route. For example, the pharmaceutical composition according to the present invention may be administered by the intramuscular, intravenous, intracutaneous, or subcutaneous route. A pharmaceutical composition or preparation to be administered parenterally may be formulated by dissolving, suspending, or emulsifying any compound or mixtures thereof, in a suitable aqueous or fat-based solvent such as, for example, a vegetable oil, a glyceride with a fatty acid, an ester of a higher fatty acid using commonly used pharmaceutical techniques. The pharmaceutical composition for parenteral use may contain at least one excipient or carrier such as, for example, a solubilizing agent, a suspending agent, an emulsifier, a stabilizer, and a preservative.
In certain embodiments, such compositions and preparations may contain at least 0.1% of the compound of formula (I). The percentage of said compound of formula (I) in these compositions may, of course, be varied and conveniently can be between about 1% and about 60% of the weight of the unit. The amount of compound in these compositions useful from a prophylactic or therapeutically point of view is such that an effective dosage, from a therapeutically or prophylactic point of view, will be
obtained.
The administration of the pharmaceutical composition according to the present invention is carried out following a protocol and at a dosage sufficient to determine the therapeutic response in the treated subject. In certain embodiments, in the pharmaceutical compositions of the present invention, the compound is formulated in dosage units. The dosage unit may contain from 0.1 to 1000 mg of a compound of formula (I) and per dosage unit for daily administration. In some embodiments, the effective amounts for the formulation will depend on the severity of the disease, disorder, or condition, on the previous therapy, on the subject’s state of health, and on the response to the drug. In some embodiments, the dose belongs to the range from 0.001% by weight to about 60% by weight of the formulation. When the compound of formula (I) or a pharmaceutically acceptable salt thereof are used in combination with one or more other active ingredients, the other active ingredients may be used in lower doses than when each one is used individually. As for the formulations relating to any variety of administration routes, the methods and formulations for administering drugs are known to those skilled in the art, for example from what is reported in Remington’s Pharmaceutical Sciences, XVII Edizione, Gennaro et at. Ed., Mack Publishing Co., 1985, and Remington’s Pharmaceutical Sciences, Gennaro AR ed. XX Edizione, 2000, Williams & Wilkins PA, USA, e Remington: The Science and Practice of Pharmacy, XXI Edition, Lippincott Williams & Wilkins Ed., 2005; and in Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, VIII Edizione. Lippincott Williams & Wilkins Ed., 2005.
The dosage of administration of the compound according to the present invention varies according to the form and route of administration and the type of disease to be treated.
By way of example, in the case of parenteral administration, the daily dosage of the compound of formula (I) may vary from 1 to 100 mg/kg of body weight.
In a further aspect, the present invention further relates to the compound according to the first aspect of the invention for use as a Dectin-1 receptor ligand or as an immunostimulating substance in a disease related to the Dectin-1 receptor.
In fact, said receptor plays a key role in the immune response to various types of diseases; the compounds according to the first aspect of the invention by performing the function of ligands of said receptor favor the activation of the immune response against said diseases. The invention is now illustrated by means of some Examples to be intended for illustrative and not limitative purposes of the same.
EXPERIMENTAL PART
Example 1 - Synthesis of cholesterol sulfate
A mixture of triethylamine-sulfur trioxide complex (0.04 mmol) and cholesterol (0.01 mmol/3.86 mg) in dimethylformamide (0.5 mL) was kept under stirring for one hour at 35°C under an argon atmosphere. Subsequently, water (0.2m L) was added and the mixture was filtered on silica gel to remove the excess of triethylamine-sulfur trioxide complex using the following eluents: petroleum ether / dichloromethane 1/1 , and subsequently methanol/dichloromethane 1/1 in which the final product was present.
After evaporation of the solvent on rotavapor, the solid residue was suspended in methanol (1 mL) and 0.5 g of Dowex Na + 50XW-8 were added; the whole was left under stirring for 3 hours at room temperature. After filtration on paper, another 0.5 g of Dowex Na + 50XW8 were added, and the product was re-filtered and evaporated under vacuum by means of a rotavapor. The sample was subsequently purified with HPLC-Rp18 using methanol as the mobile phase, obtaining 3.2 mg of cholesterol sulfate according to the invention:
Example 2 - Activity assays for cholesterol sulfate according to Examplel The cholesterol sulfate according to Example 1 was tested in a binding assay on
Dectin-1 reporter cells to evaluate a possible receptor interaction. The data for Dectin-1 activation were then compared with the values of the standard Zymosan, a Dectin-1 ligand. The assays showed a more efficient receptor binding for cholesterol sulfate as compared to Zymosan (Figure 1). Furthermore, cholesterol sulfate induced the maturation of moDC and D1 dendritic cells, as evident from the expression of typical surface phenotypic markers (Figures 2-3). The gene expression of various interleukins was also evaluated (Figures 4-5) highlighting a down-regulation effect for these proteins by cholesterol sulfate, therefore responsible for a possible ‘anergenic’ maturation of dendritic cells which potentially favors a more balanced immunogenic response and faster restoration of cellular homeostasis.
Based on this evidence, it was therefore possible to conclude that cholesterol sulfate according to Example 1 is suitable to play the role of Dectin-1 receptor ligand, thus allowing a use of the compound according to the present invention for the prevention and treatment of fungal, inflammatory, and tumor diseases.
Example 3 - Synthesis of cholestanol sulfate
A mixture of triethylamine-sulfur trioxide complex (0.04 mmol) and cholestanol (0.01 mmol/3.86 mg) in dimethylformamide (0.5 ml.) was kept under stirring for one hour at 35°C under an argon atmosphere. Subsequently, water (0.2m L) was added and the mixture was filtered on silica gel to remove the excess of triethylamine-sulfur trioxide complex using the following eluents: petroleum ether / dichloromethane 1/1 , and subsequently methanol / dichloromethane 1/1 , in which the final product was present. After evaporation of the solvent on rotavapor, the solid residue was suspended in methanol (1 ml.) and 0.5 g of Dowex Na + 50XW-8 were added; the whole was left under stirring for 3 hours at room temperature. After filtration on paper, another 0.5 g of Dowex Na + 50XW8 were added, and the product was re-filtered and evaporated under vacuum by means of a rotavapor. The sample was subsequently purified with FIPLC-Rp18 using methanol as the mobile phase, obtaining 3.2 mg of cholestanol sulfate according to the invention:
Example 4 - Binding assays on Dectin-1 reporter cells for cholestanol sulfate according to Example 3
The cholestanol sulfate according to Example 3 was tested in a binding assay on Dectin-1 reporter cells to evaluate a possible receptor interaction. The data for Dectin-1 activation were then compared with the values of the standard Zymosan, a Dectin-1 ligand. The tests showed a binding to the receptor for cholestanol sulfate (Figure 2). Based on this evidence, it was therefore possible to conclude that cholestanol sulfate according to Example 3 is suitable to play the role of Dectin-1 receptor ligand, thus allowing a use of the compound according to the present invention for the prevention and treatment of fungal, inflammatory, and tumor diseases.
Example 5 - Synthesis of β-sulfoquinovosyl-cholesterol β-Sulfoquinovosyl-cholesterol was synthesized following the procedure inspired by Manzo et al. and Ziaco et a/. (1 -Marcello Ziaco, Laura Fioretto, Genoveffa Nuzzo, Angelo Fontana, Emiliano Manzo “Short gram-scale synthesis of Sulfavant A” Organic Process Research & Development (ACS) (ISSN): 1083-6160, 2020, 24(11), 2728-2733; doi: 10.1021 /acs.oprd.0c00393; 2-Emiliano Manzo, Laura Fioretto, Dario Pagano, Genoveffa Nuzzo, Carmela Gallo, Raffaele De Palma and Angelo Fontana “Chemical synthesis of marine-derived sulfoglycolipids, a new class of molecular adjuvants”. Marine Drugs (ISSN): 16603397), 2017, 15 (9), 288. doi: 10.3390/md15090288) and shown in Scheme 1.
Schema 1. Synthesis of β-sulfoquinovosyl-cholesterol
Example 6 - Binding assays on Dectin-1 reporter cells for β-sulfoquinovosyl- cholesterol according to Example 5
The β-sulfoquinovosyl-cholesterol according to Example 5 was tested in a binding assay on Dectin-1 reporter cells to evaluate a possible receptor interaction. The data for Dectin-1 activation were then compared with the values of the standard Zymosan, a Dectin-1 ligand. The tests showed a binding to the receptor for β- sulfoquinovosyl-cholesterol (Figure 3). Based on this evidence, it was therefore possible to conclude that β-sulfoquinovosyl-cholesterol according to Example 5 is suitable to play the role of Dectin-1 receptor ligand, thus allowing a use of the compound according to the present invention for the prevention and treatment of fungal, inflammatory, and tumor diseases.
Claims
1. A compound of formula (I)
wherein: R1 is selected from the group consisting of: CH(CH3)CH2CH2R2 and CH(CH3)CHCHCHR3CHR4CH3, R2 being CH2CH(CH3)2, R3 being selected from H and CH3, and CH2CH3, and R4 being selected from CH3 and CH(CH3)2; R5 is selected from the group consisting of: OC(O)R6, OSO3H, SO3H, OPO3H2, OPO3(CH3)2, PO3H2; monosaccharyl, R6 being a Ci-C2o alkyl group;
A and B independently represent a single bond or a double bond; or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a fungal disease, an inflammatory disease, a tumor disease, or for use as an adjuvant for a vaccine.
2. The compound for use according to claim 1 , wherein R1 is CH(CH3)CH2CH2R2 and R2 is CH2CH(CH3)2.
3. The compound for use according to claim 1 or 2, wherein R5 is selected from the group consisting of: OSO3H, SO3H, OPO3H2, OPO3(CH3)2, PO3H2.
4. The compound for use according to claim 3, wherein R5 is selected from the group consisting of: OSO3H, OPO3H2, and OPO3(CH3)2
5. The compound for use according to claim 4, wherein R5 is OSO3H.
6. The compound for use according to any one of claims 1 to 5, wherein A represent a double bond, and B represent a single bond.
7. The compound for use according to claim 1 , selected from the group consisting of:
- stigmasterol sulfate
- ergosterol sulfate:
- β-sulfoquinovosyl-cholesterol:
or a pharmaceutically acceptable salt thereof.
8. The compound for use according to claim 1 , wherein said compound is cholesterol sulfate:
or a pharmaceutically acceptable salt thereof.
9. The compound for use according to any one of claims 1 to 8, wherein said fungal disease is selected from the group consisting of: candidiasis, aspergillosis, mucormycosis, fusariosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, cryptococcosis, penicillosis, and pneumocytosis.
10. The compound for use according to any one of claims 1 to 8, wherein said inflammatory disease is a diffuse inflammatory disease related to a pathogen infection or to an autoimmune response, preferably selected from the group consisting of: arthritis, colitis, allergy, sepsis, septic shock, and an autoimmune disease.
11. The compound for use according to any one of claims 1 to 8, wherein said tumor is selected from the group consisting of: carcinoma, sarcoma, melanoma, and myeloma.
12. A pharmaceutical composition comprising at least one compound of formula (I)
wherein:
R1 is selected from the group consisting of: CH(CH3)CH2CH2R2 and CH(CH3)CHCHCHR3CHR4CH3, R2 being CH2CH(CH3)2, R3 being selected from H and CH3, and R4 being selected from CH3 and CH(CH3)2; R5 is selected from the group consisting of: OC(O)R6, OSO3H, S03H, OPO3H2, OPO3(CH3)2, PO3H2; monosaccharyl, R6 being a C1-C20 alkyl group;
A and B independently represent a single bond or a double bond; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. The pharmaceutical composition according to claim 12, wherein R1 is CH(CH3)CH2CH2R2 and R2 is CH2CH(CH3)2.
14. The pharmaceutical composition according to claim 12 or 13, wherein R5 is selected from the group consisting of: OSO3H, SO3H, OPO3H2, OPO3(CH3)2, PO3H2.
15. The pharmaceutical composition according to claim 14, wherein R5 is selected from the group consisting of: OSO3H, OPO3H2, and OPO3(CH3)2
16. The pharmaceutical composition according to claim 15, wherein R5 is OSO3H.
17. The pharmaceutical composition according to any one of claims 12 to 16, wherein A represents a double bond, and B represents a single bond.
18. The pharmaceutical composition according to claim 12, wherein said compound is selected from the group consisting of:
- stigmasterol sulfate
β-sulfoquinovosyl-cholesterol:
- cholestanol sulfate:
- cholesterol sulfate:
or a pharmaceutically acceptable salt thereof.
19. The pharmaceutical composition according to claim 12, wherein said compound is cholesterol sulfate:
or a pharmaceutically acceptable salt thereof.
20. A compound according to formula (I)
wherein: R1 is selected from the group consisting of: CH(CH3)CH2CH2R2 and CH(CH3)CHCHCHR3CHR4CH3, R2 being CH2CH(CH3)2, R3 being selected from H and CH3, and R4 being selected from CH3 and CH(CH3)2; R5 is selected from the group consisting of: OC(O)R6, OSO3H, SO3H, OPO3H2, OPO3(CH3)2, PO3H2; monosaccharyl, R6 being a C1-C20 alkyl group; A and B independently represent a single bond or a double bond; or a pharmaceutically acceptable salt thereof, for use as a Dectin-1 receptor ligand or as an immunostimulating substance in the treatment of a disease related to Dectin-1 receptor.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT102021000014747A IT202100014747A1 (en) | 2021-06-07 | 2021-06-07 | STEROLIC DERIVATIVES AS NEW LIGANDS OF THE DECTIN-1 RECEPTOR IN THE THERAPEUTIC TREATMENT OF DISEASES RELATED TO THIS RECEPTOR |
| PCT/IB2022/055271 WO2022259129A1 (en) | 2021-06-07 | 2022-06-07 | Sterol derivatives as new dectin-1 receptor ligands in the therapeutic treatment of diseases related to said receptor |
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| EP4351587A1 true EP4351587A1 (en) | 2024-04-17 |
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| EP22735029.5A Pending EP4351587A1 (en) | 2021-06-07 | 2022-06-07 | Sterol derivatives as new dectin-1 receptor ligands in the therapeutic treatment of diseases related to said receptor |
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| US10293056B1 (en) * | 2000-05-24 | 2019-05-21 | Board Of Regents, The University Of Texas System | Methods and compositions for non-viral gene therapy for treatment of hyperproliferative diseases |
| CA2438960A1 (en) * | 2001-02-23 | 2002-09-06 | Glaxosmithkline Biologicals S.A. | Influenza vaccine formulations for intradermal delivery |
| MXPA05008051A (en) * | 2003-01-29 | 2005-09-21 | Pfizer Prod Inc | Canine vaccines against bordetella bronchiseptica. |
| EP2575878B1 (en) * | 2010-05-28 | 2018-06-13 | Zoetis Belgium S.A. | Vaccines comprising cholesterol and cpg as sole adjuvant-carrier molecules |
| CN104225591A (en) * | 2014-09-15 | 2014-12-24 | 兰州大学 | Immunologic adjuvant and vaccine containing immunologic adjuvant |
| US10195261B2 (en) * | 2014-11-26 | 2019-02-05 | VaxLiant, LLC | Adjuvant compositions and related methods |
| EP3713548A4 (en) * | 2017-11-21 | 2021-06-23 | Icahn School of Medicine at Mount Sinai | PROMOTING TRAINED IMMUNITY WITH THERAPEUTIC NANOBIOLOGICAL COMPOSITIONS |
| EP3692984A1 (en) * | 2019-02-08 | 2020-08-12 | Deutsches Krebsforschungszentrum, Stiftung des öffentlichen Rechts | Annexin-coated particles |
| US11273124B2 (en) * | 2019-05-23 | 2022-03-15 | Brown University | Antifungal nanoparticles for targeted treatment of fungal infections |
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