FR3041529A1 - COMPOSITIONS USEFUL FOR THE TREATMENT OF ARBOVIROSES - Google Patents
COMPOSITIONS USEFUL FOR THE TREATMENT OF ARBOVIROSES Download PDFInfo
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- FR3041529A1 FR3041529A1 FR1559010A FR1559010A FR3041529A1 FR 3041529 A1 FR3041529 A1 FR 3041529A1 FR 1559010 A FR1559010 A FR 1559010A FR 1559010 A FR1559010 A FR 1559010A FR 3041529 A1 FR3041529 A1 FR 3041529A1
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- virus
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Classifications
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Composition comprenant au moins un composé ayant un impact sur le taux cholestérol, ledit composé étant choisi parmi les inhibiteurs de la synthèse du cholestérol et les inhibiteurs du transport intracellulaire du cholestérol (par exemple inhibiteurs de NPC1 et/ou NPC2) et leurs mélanges, pour son utilisation dans le traitement ou la prévention des infections virales dues à un arbovirus chez un mammifère humain ou non humain.Composition comprising at least one compound having an impact on the cholesterol level, said compound being chosen from inhibitors of cholesterol synthesis and inhibitors of intracellular cholesterol transport (for example NPC1 and / or NPC2 inhibitors) and their mixtures, for its use in the treatment or prevention of viral infections due to an arbovirus in a human or non-human mammal.
Description
COMPOSITIONS UTILES POUR LE TRAITEMENT DES ARBOVIROSESCOMPOSITIONS USEFUL FOR THE TREATMENT OF ARBOVIROSES
Les arboviroses sont des affections transmises par des arthropodes hématophages. Elles sont dues à des arbovirus, virus habituellement transmis, dans les conditions naturelles, de vertébré à vertébré, par un arthropode hématophage, qui en constitue le vecteur. Elles regroupent des maladies différentes quant à leur symptomatologie et surtout leur épidémiologie. Cent dix virus environ sont pathogènes pour l'homme et une quarantaine d'entre eux est cause de maladies animales identifiées. A la suite de l'injection de salive lors de la piqûre d'un arthropode infestant, le vertébré réceptif va développer une infection arbovirale. Le virus va se répliquer à proximité du point d'inoculation, puis dans les ganglions lymphatiques correspondants : c'est la phase de virémie. Puis, le virus va disséminer dans l'organisme jusqu'aux organes cibles. L'infection entraîne une réponse immune à la fois humorale et cellulaire.Arboviruses are diseases transmitted by blood-sucking arthropods. They are caused by arboviruses, a virus that is usually transmitted in natural conditions from vertebrate to vertebrate, by a haematophagous arthropod, which is its vector. They group different diseases as to their symptoms and especially their epidemiology. About one hundred and ten viruses are pathogenic for humans and about forty of them cause animal diseases identified. Following the injection of saliva during the bite of an infective arthropod, the receptive vertebrate will develop an arboviral infection. The virus will replicate near the point of inoculation, then in the corresponding lymph nodes: this is the phase of viremia. Then, the virus will spread in the body to the target organs. The infection causes an immune response that is both humoral and cellular.
La prophylaxie générale des arboviroses repose sur la surveillance des foyers épidémiologiques (humains, vertébrés et vecteurs), la lutte antivectorielle et la protection de la population humaine réceptive par les moustiquaires, les répulsifs et les vaccinations limitées actuellement au vaccin anti-amaril et au vaccin contre l'Encéphalite japonaise.The general prophylaxis of arboviruses is based on surveillance of epidemiological foci (human, vertebrate and vector), vector control and protection of the susceptible human population by mosquito nets, repellents and vaccinations currently limited to yellow fever vaccine and vaccine. against Japanese Encephalitis.
Parmi les arboviroses les plus importantes en terme de santé publique, on retrouve, le chikungunya qui est une maladie infectieuse tropicale, due à l'arbovirus CHIKV (Chikungunya Virus), un alphavirus de la famille des Togaviridae, transmise par des moustiques du genre Aedes.Among the most important arboviroses in terms of public health, there is the chikungunya which is a tropical infectious disease, due to the arbovirus CHIKV (Chikungunya Virus), an alphavirus of the family of Togaviridae, transmitted by mosquitoes of the genus Aedes .
De nombreux foyers endémiques ont été répertoriés lors des cinquantes dernières années dans de nombreux pays d'Afrique, par exemple au Niger, au Sénégal, en République Démocratique du Congo, au Cameroun, au Gabon, en Ouganda, au Zimbabwe et au Nigeria. Le virus est également présent au Pakistan et en Inde où les émergences sont régulières depuis une cinquante d’années. En 2005-2006, une importante épidémie de chikungunya a frappé les îles de l'Océan Indien, notamment l'île de La Réunion, avec plusieurs centaines de milliers de cas. Actuellement, il n'existe ni vaccin ni traitement contre cette maladie.Numerous endemic foci have been recorded in the last fifty years in many African countries, for example in Niger, Senegal, the Democratic Republic of Congo, Cameroon, Gabon, Uganda, Zimbabwe and Nigeria. The virus is also present in Pakistan and India, where emergence has been regular for fifty years. In 2005-2006, a major chikungunya outbreak hit the Indian Ocean islands, including Reunion Island, with several hundred thousand cases. Currently, there is no vaccine or treatment for this disease.
Aussi existe-t-il un besoin de mettre au point un traitement efficace contre ces arboviroses, notamment contre le CHIKV.There is also a need to develop an effective treatment against these arboviruses, especially against CHIKV.
Or les Inventeurs se sont aperçus que malgré l'importance de la barrière cutanée comme site d'entrée des arbovirus, les connaissances acquises autour du système immunitaire de la peau vis-à-vis des arbovirus ainsi que les voies empruntées par le virus demeuraient succinctes. Aussi, dans ce cadre, les Inventeurs ont réalisé une étude protéomique comparative de fibroblastes cutanés infectés ou non par le virus chikungunya par la méthode SILAC (stable isotope labeling by/with amino acids in cell culture) développée par Ong S.E. et al.{Mol. Cell. Proteomics (2002), 1(5), p 376-386). Ils ont identifié dans cette analyse que les protéines Niemann-Pick type C (NPC1 et NPC2) étaient essentielles à la réplication du CHIKV dans les fibroblastes car quand ces dernières sont mutées les Inventeurs ont observé une réduction drastique de l'infection virale. Lorsque ces protéines sont mutées le transport lipidique intracellulaire est interrompu, conduisant à l’accumulation de cholestérol et de sphingolipides dans les endosomes et les lysosomes.However the inventors have realized that despite the importance of the skin barrier as an arbovirus entry site, the knowledge acquired around the immune system of the skin vis-à-vis the arboviruses as well as the routes taken by the virus remained succinct . Also, in this context, the inventors have carried out a comparative proteomic study of cutaneous fibroblasts infected or not by the chikungunya virus by the SILAC method (stable isotope-labeling by / with amino acids in cell culture) developed by Ong SE et al. . Cell. Proteomics (2002), 1 (5), p 376-386). They identified in this analysis that the Niemann-Pick type C proteins (NPC1 and NPC2) were essential for the replication of CHIKV in fibroblasts because when they are mutated the inventors have observed a drastic reduction in the viral infection. When these proteins are mutated, intracellular lipid transport is interrupted, leading to the accumulation of cholesterol and sphingolipids in endosomes and lysosomes.
La perte de fonctionnalité de la protéine NPC1 ou de la protéine NPC2 provoque la maladie de Niemann-Pick type C, un désordre rare du stockage lipidique neuroviscéral lié à l'interruption du transport lipidique intracellulaire qui conduit à l’accumulation de cholestérol et de sphingolipides dans les endosomes et les lysosomes. Par ailleurs, le transport intracellulaire du cholestérol contrôlé par la protéine NPC1 est nécessaire à la production efficace de virions de VIH-1 et cette protéine NPC1 semble être indispensable à l’entrée dans la cellule hôte du virus Ebola et du virus Marburg qui sont des filovirus. Cependant à ce jour, aucune étude n'a montré une relation entre les alphavirus et les protéines NPC1 et NPC2.Loss of functionality of NPC1 protein or NPC2 protein causes Niemann-Pick type C disease, a rare neurovisceral lipid storage disorder related to interruption of intracellular lipid transport that leads to the accumulation of cholesterol and sphingolipids in endosomes and lysosomes. Furthermore, the intracellular transport of NPC1-controlled cholesterol is necessary for the efficient production of HIV-1 virions and this NPC1 protein appears to be essential for entry into the host cell of Ebola virus and Marburg virus, which are filoviruses. However, to date, no study has shown a relationship between alphaviruses and NPC1 and NPC2 proteins.
Aussi la présente invention a pour objet une composition comprenant au moins un composé ayant un impact sur le taux cholestérol, ledit composé étant choisi parmi les inhibiteurs de la synthèse du cholestérol et les inhibiteurs des transporteurs intracellulaires du cholestérol et leurs mélanges pour son utilisation dans le traitement ou la prévention des infections virales dues à un arbovirus chez un mammifère humain ou non humain.Also the subject of the present invention is a composition comprising at least one compound having an impact on the cholesterol level, said compound being chosen from inhibitors of cholesterol synthesis and inhibitors of intracellular cholesterol transporters and their mixtures for use in the treatment of cholesterol. treatment or prevention of viral infections due to an arbovirus in a human or non-human mammal.
Au sens de l'invention, la composition peut comprendre soit un ou plusieurs inhibiteurs de la synthèse du cholestérol, soit un ou plusieurs inhibiteurs du transport intracellulaire du cholestérol, soit un mélange de un ou plusieurs inhibiteurs de la synthèse du cholestérol avec un ou plusieurs inhibiteurs du transport intracellulaire du cholestérol.Within the meaning of the invention, the composition may comprise one or more inhibitors of cholesterol synthesis, or one or more inhibitors of intracellular cholesterol transport, or a mixture of one or more inhibitors of cholesterol synthesis with one or more inhibitors of intracellular cholesterol transport.
Au sens de la présente invention on entend par inhibiteurs des transporteurs du cholestérol, tout composé qui, soit inhibe au moins l'une des protéines NPC1 et NPC2 intervenant dans le transport intracellulaire des lipides, notamment du cholestérol, soit qui entraîne une déficience d'au moins une des dites protéines, soit qui présente au niveau cellulaire un phénotype proche de celui des cellules présentant des mutations dans la protéine NPC1 et/ou NPC2.For the purposes of the present invention, the term "cholesterol transporter inhibitors" means any compound which either inhibits at least one of the NPC1 and NPC2 proteins involved in the intracellular transport of lipids, in particular cholesterol, or which causes a deficiency of at least one of said proteins, which has a cell-like phenotype close to that of cells with mutations in the NPC1 and / or NPC2 protein.
Au sens de la présente invention, on entend par mammifère non humain notamment les bovins, les chevaux, les chiens, les ovins et les félins.For the purposes of the present invention, the term "non-human mammal" includes cattle, horses, dogs, sheep and felines.
Dans un mode de réalisation avantageux de l'invention, les inhibiteurs de la synthèse du cholestérol sont choisis dans le groupe comprenant les statines. A titre de statine on peut citer la simvastatine, la pravastatine, la fluvastatine, l'atorvastatine, la rosuvastatine et la cérivastatine.In an advantageous embodiment of the invention, the inhibitors of cholesterol synthesis are chosen from the group comprising statins. As a statin, mention may be made of simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and cerivastatin.
Dans un mode de réalisation avantageux de l'invention, les inhibiteurs du transport du cholestérol sont choisis dans le groupe comprenant notamment l'imipramine et ses dérivés. L'imipramine est déjà utilisée en clinique comme antidépresseur, du fait de son action inhibitrice sur la capture neuronale des catécholamines et de la sérotonine. C’est le premier-né de la famille des antidépresseurs tricycliques dont les propriétés ont été découvertes par Roland Kuhn en 1957. Les inventeurs ont montré de manière surprenante que l'imipramine conduit à un phénotype cellulaire proche de celui des cellules possédant des mutations dans les protéines NPC1 et NPC2.In an advantageous embodiment of the invention, the cholesterol transport inhibitors are chosen from the group comprising in particular imipramine and its derivatives. Imipramine is already used clinically as an antidepressant because of its inhibitory action on the neuronal capture of catecholamines and serotonin. It is the firstborn in the family of tricyclic antidepressants whose properties were discovered by Roland Kuhn in 1957. The inventors have surprisingly shown that imipramine leads to a cellular phenotype similar to that of cells with mutations in NPC1 and NPC2 proteins.
Dans un mode de réalisation avantageux de l'invention, l'arbovirus appartient à la famille des Togaviridae ou des Flaviridae et est notamment un alphavirus. On peut citer comme alphavirus le virus du chikungunya, le virus de Sindbis, le virus de la forêt de Semliki, le virus O’nyong’nyong, le virus Mayaro, le virus de la Ross River, le virus de la forêt de Barmah, le virus de l'encéphalite équine de l'Est, le virus de l'encéphalite équine de l'Ouest et le virus de l'encéphalite équine du Venezuela et comme flavivirus le virus de la dengueIn one advantageous embodiment of the invention, the arbovirus belongs to the Togaviridae or Flaviridae family and is in particular an alphavirus. Examples of alphaviruses include chikungunya virus, Sindbis virus, Semliki forest virus, O'nyong'nyong virus, Mayaro virus, Ross River virus, Barmah forest virus, Eastern equine encephalitis virus, western equine encephalitis virus and Venezuelan equine encephalitis virus, and dengue virus flaviviruses
Dans un autre mode de réalisation avantageux de l'invention, la composition est une composition pharmaceutique et comprend en outre au moins un excipient pharmaceutiquement acceptable. Ces excipients sont ceux classiquement utilisés et l'homme du métier saura choisir l'excipient approprié. On peut citer à titre d'exemple, les agents de désintégration ou délitants, les liants, les charges et les lubrifiants. Des exemples de délitants comprennent l'agar-agar, les alginates, le carbonate de calcium, la carboxyméthylcellulose, la cellulose, les argiles, le dioxyde de silicium colloïdal, la croscarmellose sodique, la crospovidone, les gommes, le silicate de magnésium et d'aluminium, la méthylcellulose, la polacriline potassium, l'alginate de sodium, l'hydroxypropylcellulose faiblement substituée, la polyvinylpyrrolidone réticulée, l'hydroxypropylcellulose et l'amidon. Des exemples de liants comprennent la cellulose microcristalline, l'hydroxyméthylcellulose, l'hydroxypropylcellulose et la polyvinylpyrrolidone. Des exemples de charges comprennent le carbonate de calcium, le phosphate de calcium, le phosphate de calcium dibasique, le sulfate de calcium tribasique, la carboxyméthylcellulose de calcium, la cellulose, les dérivés de la dextrine, la dextrine, le dextrose, le fructose, le lactitol, le lactose, le carbonate de magnésium, l'oxyde de magnésium, le maltitol, les maltodextrines, le maltose, le sorbitol, l'amidon, le saccharose et le xylitol. Des exemples de lubrifiants comprennent l’agar, le stéarate de calcium, l’oléate d’éthyle, le lauréate d'éthyle, le glycérol, le palmitostéarate de glycéryle, les huiles végétales hydrogénées, l’oxyde de magnésium, le stéarate de magnésium, le mannitol, le poloxamère, les glycols, le benzoate de sodium, le laurylsulfate de sodium, le stéarylfumarate de sodium, le sorbitol, l’acide stéarique, le talc et le stéarate de zinc.In another advantageous embodiment of the invention, the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient. These excipients are those conventionally used and those skilled in the art will be able to choose the appropriate excipient. By way of example, disintegrating agents or disintegrants, binders, fillers and lubricants may be mentioned. Examples of disintegrants include agar, alginates, calcium carbonate, carboxymethylcellulose, cellulose, clays, colloidal silicon dioxide, croscarmellose sodium, crospovidone, gums, magnesium silicate, and the like. aluminum, methylcellulose, polacrilin potassium, sodium alginate, low substituted hydroxypropylcellulose, crosslinked polyvinylpyrrolidone, hydroxypropylcellulose and starch. Examples of binders include microcrystalline cellulose, hydroxymethylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone. Examples of fillers include calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose and xylitol. Examples of lubricants include agar, calcium stearate, ethyl oleate, ethyl laurate, glycerol, glyceryl palmitostearate, hydrogenated vegetable oils, magnesium oxide, magnesium stearate mannitol, poloxamer, glycols, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, sorbitol, stearic acid, talc and zinc stearate.
Dans un autre mode de réalisation avantageux de l'invention, l'imipramine et ses dérivés sont utilisés sous forme de base ou de sels. On peut citer à titre d'exemple de sels d'imipramine, le chlrohydrate et le méthane sulfonate.In another advantageous embodiment of the invention, imipramine and its derivatives are used in base form or salts. Examples of imipramine salts are the hydrochloride and the methanesulfonate.
Dans un autre mode de réalisation avantageux de l'invention la composition se présente sous une forme adaptée à une administration par voie orale, rectale ou parentérale. Toutes ces formes sont bien connues de l'homme du métier. A titre d'exemple on peut citer pour l'administration par voie orale, les comprimés, les capsules, les gélules, les granules, les granulés, les pastilles, les comprimés à libération prolongée, les solutions, les émulsions, les suspensions, les poudres orales. A titre d'exemple on peut citer pour l'administration par voie rectale les suppositoires et les ovules. A titre d'exemple on peut citer pour l'administration par voie parentérale, les solutions, les suspensions et les perfusions.In another advantageous embodiment of the invention the composition is in a form suitable for oral, rectal or parenteral administration. All these forms are well known to those skilled in the art. By way of example, mention may be made, for oral administration, of tablets, capsules, capsules, granules, granules, lozenges, prolonged-release tablets, solutions, emulsions, suspensions, oral powders. By way of example, the rectal administration of suppositories and eggs may be mentioned. By way of example, parenteral administration may include solutions, suspensions and infusions.
Toutes ces formes seront adaptées pour une administration journalière en une ou plusieurs doses. La dose varie en fonction du mode d'administration, de l'âge, du poids et de l'état général du sujet et le médecin ou le vétérinaire saura décider la dose appropriée et le régime d'administration.All these forms will be adapted for daily administration in one or more doses. The dose varies according to the method of administration, the age, the weight and the general condition of the subject and the doctor or the veterinarian will be able to decide the appropriate dose and the administration regime.
Les différentes compositions et les différentes formes d'administration sont préparées par des techniques connues de l'homme du métier.The different compositions and the different forms of administration are prepared by techniques known to those skilled in the art.
La présente invention a également pour objet, une méthode de traitement ou de prévention des infections virales dues à un arbovirus chez un mammifère humain ou non humain comprenant l'administration au dit mammifère d'une dose efficace d'un composé choisi parmi les inhibiteurs de la synthèse du cholestérol et les inhibiteurs des transporteurs intracellulaires du cholestérol et leurs mélanges.The present invention also relates to a method for treating or preventing arbovirus viral infections in a human or non-human mammal comprising administering to said mammal an effective dose of a compound selected from the group consisting of cholesterol synthesis and inhibitors of intracellular cholesterol transporters and their mixtures.
La présente invention a également pour objet une trousse ou un kit comprenant un ou plusieurs récipients, chacun de ses récipients contenant une composition selon l'invention. Conformément à l'invention chaque récipient peut contenir des compositions identiques ou différentes, lesdites compositions comprenant au moins un inhibiteur de la synthèse du cholestérol ou au moins un inhibiteur des transporteurs intracellulaires du cholestérol ou des mélanges de ceux-ci. La trousse ou le kit peut en outre comprendre des instructions pour l'administration desdites compositions pour la prévention et le traitement des arboviroses.The present invention also relates to a kit or a kit comprising one or more containers, each of its containers containing a composition according to the invention. According to the invention each container may contain the same or different compositions, said compositions comprising at least one inhibitor of cholesterol synthesis or at least one inhibitor of intracellular cholesterol transporters or mixtures thereof. The kit or kit may further comprise instructions for administering said compositions for the prevention and treatment of arboviruses.
Les exemples 1 à 3 et les figures 1 à 5 qui suivent illustrent l'invention.Examples 1 to 3 and Figures 1 to 5 which follow illustrate the invention.
La figure 1 montre les protéines du compartiment endosome/lysosome surexprimées dans les cellules infectées par le CHIKV. CTSB : cathepsine B ; CTSC : cathepsine C ; CTSD : cathepsine D ; CTSZ : cathepsine Z ; SDCBP : Syntenine (Syndecan Binding Protein) ; NCSTN : nicastrine ; LAMP 1 : protéine membranaire 1 associée au lysosome (Lysosomal-associated membrane protein 1); LAMP 2 : protéine membranaire 2 associée au lysosome Lysosomal-associated membrane protein 2 ; NPC 1 protéine Niemann-Pick type C 1 ; NPC 2 protéine Niemann-Pick type C2 ; NAPA : protéine d'attachement au facteur sensible au N-ethylmaleimide (N-ethylmaleimide-sensitive factor Attachment Protein Alpha) ;Figure 1 shows the endosome / lysosome compartment proteins overexpressed in CHIKV infected cells. CTSB: cathepsin B; CTSC: cathepsin C; CTSD: cathepsin D; CTSZ: cathepsin Z; SDCBP: Syntenin (Syndecan Binding Protein); NCSTN: nicastrin; LAMP 1: Membrane protein 1 associated with lysosome (Lysosomal-associated membrane protein 1); LAMP 2: Membrane Protein 2 Associated with Lysosomal Lysosomal-associated Membrane Protein 2; NPC 1 protein Niemann-Pick type C 1; NPC 2 protein Niemann-Pick type C2; NAPA: attachment protein to N-ethylmaleimide-sensitive factor (N-ethylmaleimide-sensitive factor Attachment Protein Alpha);
La figure 2 représente le pourcentage de cellules infectées visualisé par cytométrie en flux après infection par le CHIKV de cellules fibroblastes saines (a) et des cellules ayant des mutations au niveau des protéines NPC1 (b) ou NPC2 (c) selon l'exemple 2.FIG. 2 represents the percentage of infected cells visualized by flow cytometry after CHIKV infection of healthy fibroblast cells (a) and cells having mutations at the NPC1 (b) or NPC2 (c) proteins according to Example 2 .
La figure 3 illustre le nombre de copies d'ARN viral (axe des ordonnées) mesuré par PCR quantitative dans des cellules fibroblastes saines infectées par le virus CHIKV (saines) et des cellules ayant des mutations au niveau des protéines NPC1 ou NPC2 conformément à l'exemple 2.FIG. 3 illustrates the number of copies of viral RNA (y-axis) measured by quantitative PCR in healthy fibroblast cells infected with the CHIKV virus (healthy) and cells having mutations at the level of the NPC1 or NPC2 proteins in accordance with FIG. Example 2
La figure 4 illustre le nombre de cellules fibroblastes infectées par en l'absence d'imipramine (0) ou en présence d'imipramine à 10, 25, 50, 75 et 100 μΜ mesuré par cytométrie en flux selon l'exemple 3.FIG. 4 illustrates the number of infected fibroblast cells in the absence of imipramine (0) or in the presence of imipramine at 10, 25, 50, 75 and 100 μΜ measured by flow cytometry according to example 3.
La figure 5 illustre le nombre de copies d'ARN viral (axe des ordonnées) mesuré par PCR quantitative dans des cellules fibroblastes infectées par le virus CHIKV en l'absence d'imipramine (0) ou en présence d'imipramine à 10, 25, 50, 75 et 100 μΜ mesuré selon l'exemple 3.FIG. 5 illustrates the number of copies of viral RNA (y-axis) measured by quantitative PCR in fibroblast cells infected with the CHIKV virus in the absence of imipramine (0) or in the presence of imipramine at 10, 25 , 50, 75 and 100 μΜ measured according to Example 3.
Exemple 1 : Identification des protéines surexprimées dans des fibroblastes cutanés infectés par le virus chikungunya 1.1. Mode opératoireExample 1 Identification of proteins overexpressed in cutaneous fibroblasts infected with the chikungunya virus 1.1. Operating mode
Une étude protéomique (Méthode SILAC) comparative de fibroblastes cutanés infectés ou non par le virus chikungunya a été réalisée. La technique SILAC est une approche de protéomique quantitative basées sur la spectrométrie de masse et le marquage métabolique des protéines.A comparative proteomic study (SILAC method) of cutaneous fibroblasts infected or not with the chikungunya virus was carried out. The SILAC technique is a quantitative proteomics approach based on mass spectrometry and metabolic labeling of proteins.
Le principe est le suivant : les cellules sont cultivées dans un milieu contenant soit des acides aminés naturels (synthèse de protéines « légères »), soit leurs équivalents isotopiquement marqués (synthèse de protéines « lourdes »). Les populations cellulaires à comparer sont mélangées et traitées comme un seul échantillon, ce qui permet de préparer les protéines d'intérêt sans risquer d'introduire des erreurs de quantification. Au cours de l'analyse par spectrométrie de masse, l'abondance relative entre les échantillons biologiques peut être calculée pour chaque protéine en comparant l'intensité des peptides légers et lourds.The principle is as follows: the cells are cultured in a medium containing either natural amino acids ("light" protein synthesis) or their isotopically labeled equivalents ("heavy" protein synthesis). The cell populations to be compared are mixed and treated as a single sample, which makes it possible to prepare the proteins of interest without the risk of introducing quantification errors. During mass spectrometry analysis, the relative abundance between biological samples can be calculated for each protein by comparing the intensity of light and heavy peptides.
Dans notre étude, les cellules fibroblastes (lignée HFF-1) marquées (milieu lourd) ou non (milieu léger) avec de l’arginine et de la lysine lourdes ont été infectées par le CHIKV (MOI 8). 48h après infection, les protéines des différents échantillons ont été extraites. Les protéines marquées des cellules infectées et les protéines normales des cellules non infectées, ainsi que les protéines normales des cellules infectées et les protéines marquées des cellules non infectées ont été mélangées à un ratio de 1:1. Ensuite, les deux échantillons de protéines obtenus ont été séparés sur gel SDS-PAGE, les protéines totales ont été coupées en 9 bandes et elles ont été digérées à la trypsine. Enfin, les peptides obtenus ont été analysés au spectromètre de masse et les données obtenues ont été traitées avec le logiciel MaxQuant pour obtenir la quantification relative des protéines. 1.2. RésultatsIn our study, labeled fibroblast cells (HFF-1 line) (heavy medium) or not (light medium) with heavy arginine and lysine were infected with CHIKV (MOI 8). 48 hours after infection, the proteins of the different samples were extracted. The labeled proteins of the infected cells and the normal proteins of the uninfected cells, as well as the normal proteins of the infected cells and the labeled proteins of the uninfected cells were mixed at a ratio of 1: 1. Then, the two protein samples obtained were separated on SDS-PAGE gel, the total proteins were cut into 9 bands and they were digested with trypsin. Finally, the peptides obtained were analyzed by mass spectrometer and the data obtained were processed with the MaxQuant software to obtain the relative quantification of the proteins. 1.2. Results
Ils sont donnés dans la figure 1.They are given in Figure 1.
Parmi les protéines surexprimées dans les cellules infectées on trouve les protéines Niemann-Pick type C (NPC1 et NPC2).Among the proteins overexpressed in infected cells are Niemann-Pick type C proteins (NPC1 and NPC2).
Exemple 2 : Influence de la mutation des protéines NPC1 et NPC2 sur la réplication du CHIKV 2.1. Mode opératoireExample 2 Influence of the mutation of the NPC1 and NPC2 proteins on the replication of CHIKV 2.1. Operating mode
Des cellules saines et des cellules de patients atteints d'une maladie de Niemman-Pick (Niemman-Pick disease) avec soit la protéine NPC1 mutée, soit la protéine NPC2 mutée ont été fournies par la société Coriell Cell Repositories ; http://ccr.coriell.org/')· Les cellules sont mises en contact avec le CHIKV (Multiplicité d'infection ou MOI = 0,5) pendant 2h à 37°C puis les cellules sont lavées 3 fois et le milieu de culture est rajouté et les cellules sont mises à 37°C pendant 24H. Le pourcentage de cellules infectées est mesuré par cytométrie en flux et le nombre de copies d'ARN viral est mesuré par PCR quantitative. 2.2. RésultatsHealthy cells and cells of patients with Niemman-Pick disease with either mutated NPC1 protein or mutated NPC2 protein were provided by Coriell Cell Repositories; http://ccr.coriell.org/')· The cells are put in contact with the CHIKV (Multiplicity of infection or MOI = 0,5) during 2h at 37 ° C then the cells are washed 3 times and the medium culture is added and the cells are put at 37 ° C for 24H. The percentage of infected cells is measured by flow cytometry and the viral RNA copy number is measured by quantitative PCR. 2.2. Results
Ils sont donnés dans les figures 2 et 3.They are given in Figures 2 and 3.
Dans la figure 2, 50,52 % des cellules saines sont infectées, alors que seulement 16,26 % des cellules présentant une protéine NCP1 mutée et 5,28% des cellules présentant une protéine NPC2 mutée sont infectées.In Figure 2, 50.52% of the healthy cells are infected, whereas only 16.26% of the cells presenting a mutated NCP1 protein and 5.28% of the cells presenting a mutated NPC2 protein are infected.
Dans la figure 3, on observe une réduction de 72% du nombre de copies d'ARN viral dans les cellules ayant la protéine NPC1 mutée et 92% de l'infection dans les cellules ayant la protéine NPC2 mutée comparativement aux cellules saines.In Figure 3, there is a 72% reduction in the number of viral RNA copies in cells with the mutated NPC1 protein and 92% of the infection in cells with the mutated NPC2 protein compared to healthy cells.
Exemple 3 Effet de l'imipramine sur des cellules fibroblastesExample 3 Effect of Imipramine on Fibroblast Cells
infectées par le CHIVK 3.1. Mode opératoireinfected with CHIVK 3.1. Operating mode
Des fibroblastes cutanés sont traités par de l'imipramine à différentes concentration 10, 25, 50, 75 et 100 μΜ pendant 2H à 37°C. Les cellules sont ensuite exposées au CHIKV pendant 2h (en présence d'imipramine) puis elles sont lavées et mises en présence de milieu de culture pendant 24H (en présence d'imipramine). L'infection virale a ensuite été évaluée par cytométrie en flux et le nombre de copies d'ARN viral par PCR quantitative. 3.2. RésultatsSkin fibroblasts are treated with imipramine at different concentrations of 10, 25, 50, 75 and 100 μΜ for 2 h at 37 ° C. The cells are then exposed to CHIKV for 2 h (in the presence of imipramine) and then washed and placed in the presence of culture medium for 24 hours (in the presence of imipramine). Viral infection was then assessed by flow cytometry and viral RNA copy number by quantitative PCR. 3.2. Results
Ils sont donnés dans les figures 4 et 5.They are given in Figures 4 and 5.
Contrairement aux cellules infectées en absence d'imipramine on observe une réduction de l'infection en présence d'imipramine de manière dose dépendante, jusqu'à atteindre 100 % d'inhibition de l'infection des cellules par le CHIKV pour une concentration de 100 μΜ (Figure 4).In contrast to infected cells in the absence of imipramine, a reduction in imipramine infection is observed in a dose-dependent manner, up to 100% inhibition of CHIKV infection of the cells for a concentration of 100. μΜ (Figure 4).
De la même manière on observe en présence d'imipramine une diminution de l'infection des cellules de manière dose dépendante et on arrive à totalement bloquer l'infection à partir de 75 pM d'imipramine (Figure 5).In the same way, in the presence of imipramine, a reduction in the infection of the cells is observed in a dose-dependent manner and the infection is completely blocked from 75 μM imipramine (FIG. 5).
Ainsi l'imipramine est efficace sur l'infection au CHIKV à des concentrations où elle n'est pas cytotoxique.Thus imipramine is effective on CHIKV infection at concentrations where it is not cytotoxic.
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