Dicarboxylic acids and esters thereof for use in the treatment of a viral lung infection

Abstract

The present invention relates to a compound of formula (I) for use in a method of treatment of a viral lung infection and / or of an adverse immune response to a viral lung infection, the method comprising administering to a subject in need thereof an effective amount of said compound, or to a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable support for use in a method as defined above.

Description

[0001] COMPOUNDS FOR THE TREATMENT OF A LUNG VIRAL INFECTION

[0002] Background

[0003] Lung infections can be either a persistent and pervasive burden, such as influenza infections, or a sudden worldwide disruptive outbreak, such as SARS-CoV-2. This recent pandemic has shed new light on the critical importance of viruses in respiratory infections.

[0004] Influenza A virus (IAV) causes significant morbi / mortality each year, since the 1918 pandemic, and influenza pathogenesis as well as anti-influenza therapeutic strategies have been extensively investigated. The pathophysiology of influenza lung infection is the result of two phenomena: (i) the intrinsic viral pathogenicity, linked to its tropism for the airway cells of the host, and (ii) the adverse immune response of the subject, which usually comprises a hyper- inflammatory immune response. Indeed, a robust host immune response is required for the viral clearance but the massive cellular recruitment and release of cytotoxic molecules lead to lung hyper-inflammation and can be associated with lung damage, morbidity and death.

[0005] Current anti-lAV approaches, such as vaccination and antivirals, exhibit suboptimal effectiveness. The short duration of vaccine- induced immunity and the antigenic drift of influenza viruses compromise host protection. Additionally, skepticism persists regarding the efficacy of approved anti-influenza drugs like the neuraminidase inhibitor oseltamivir (Tamiflu®). Consequently, innovative strategies are crucial for improving influenza virus treatments.

[0006] The pathophysiology of influenza-related pneumonia stems from both viral pathogenicity and the host immune response. While a robust immune response is essential for viral clearance, excessive cellular recruitment and release of cytotoxic molecules lead to lung hyperinflammation, resulting in tissue damage, morbidity, and death.

[0007] Recent discoveries in metabolic reprogramming of immune cells have opened new therapeutic avenues for modulating immune responses. Metabolism is fundamental to all biological functions, and the integration of metabolism with immunity, known as immunometabolism, is at the forefront of immunology research.

[0008] The Applicants previous studies using mass spectrometry and nuclear magnetic resonance demonstrated significant alterations in metabolite concentrations in the lungs of mice and humans infected with IAV. Metabolites, which are small molecules typically under 1 ,000 Daltons, include sugars, amino acids, nucleotides, and lipids.

[0009] Building on this finding, the Applicants studied a series of compounds for their anti-influenza activity. Given that influenza pathophysiology involves both cytopathic viral effects and excessive inflammatory responses, the anti-inflammatory properties of these compounds was also examined. The Applicants found that some of these compounds not only allow to inhibit influenza virus replication but also exert anti-inflammatory properties that are potent enough to disrupt the inflammatory cascades during influenza. Brief description

[0010] Accordingly, an embodiment E1 of the present disclosure relates to a compound of formula (I):

[0011] Wherein

[0012] R1 is selected from C1-6 alkyl, benzene, pyridine, pyrimidine, pyrazine, pyridazine, thiophene,

[0013] R2, Rs are independently selected from H, NH2, NH(CI-6 alkyl), N( C1-6 alkyl)2, CO2Re, OH, SH, S-S-R7, halogen, SO3R8, O( Ci-6alkyl), P(O)(OH)2,

[0014] R3, R4, Re are independently selected from H, Na, K, C1-6 alkyl,

[0015] R7is a C1-6 alkyl optionally substituted by n COOH moiety, n being an integer from 1 to 12,

[0016] R8is selected from Na and K, for use in a method of treatment of a viral lung infection and / or of an adverse immune response to a viral lung infection, said method comprising administering to a subject in need thereof an effective amount of compound of formula (I) or of a pharmaceutically acceptable salt thereof.

[0017] An embodiment E2 of the present disclosure relates to a compound for use in a method according to embodiment E1 , wherein said compound is of formula (la), (lb), (Ic), (Id) or (le):

[0018] R2, Rs are independently selected from H, NH2, NH(CI-6 alkyl), N( C1-6 alkyl)2, CO2Re, OH, SH, S-S-R7, halogen, SO3R8, O( Ci-6alkyl), P(O)(OH)2,

[0019] R3, R4, Re are independently selected from H, Na, K, C1-6 alkyl,

[0020] R7is a C1-6 alkyl optionally substituted by n COOH moiety, n being an integer from 1 to 12,

[0021] R8is selected from Na and K.

[0022] An embodiment E3 of the present disclosure relates to a compound for use in a method according to embodiment E1 or E2, wherein the compound is selected from the group consisting of:

[0023] An embodiment E4 of the present disclosure relates to a compound for use in a method according to any one of embodiments E1 to E3, wherein the viral lung infection is caused by a respiratory virus preferably selected from an influenza virus, a coronavirus, a respiratory syncytial virus, a parainfluenza virus, a metapneumovirus, a rhinovirus, an adenovirus, a varicella-zoster virus, a cytomegalovirus, a paramyxovirus such as Nipah virus, an enterovirus and a bocavirus.

[0024] An embodiment E5 of the present disclosure relates to a compound for use in a method according to any one of embodiments E1 to E4, wherein the viral lung infection is caused by an influenza virus.

[0025] An embodiment E6 of the present disclosure relates to a compound for use in a method according to any one of embodiments E1 to E5, wherein the method is applied to treat the viral lung infection.

[0026] An embodiment E7 of the present disclosure relates to a compound for use in a method according to any of embodiments E1 to E6, wherein the method is applied to treat an adverse immune response to the viral lung infection.

[0027] An embodiment E8 of the present disclosure relates to a compound for use in a method according to any of one embodiments E1 to E6, wherein the method is applied to prevent a lung viral infection from escalating to an adverse immune response.

[0028] An embodiment E9 of the present disclosure relates to a compound for use in a method according to any of embodiments E1 to E8, wherein the adverse immune response to viral lung infection is selected from a hyper-inflammatory immune response, a dyspnea, a tachypnea, a pneumonia in particular an acute pneumonia, an exacerbation of a chronic respiratory disease such as asthma or chronic obstructive pulmonary disease, a sepsis, a septic shock, a cytokine storm or an acute respiratory distress syndrome (ARDS).

[0029] An embodiment E10 of the present disclosure relates to a compound for use in a method according to embodiments E1 to E9, wherein the compound is administered between 2 and 14 days post infection.

[0030] An embodiment E1 1 of the present disclosure relates to a compound for use in a method according to any one of embodiments E1 to E10, wherein the subject is an animal, preferably a human, a domestic bird or a pig.

[0031] An embodiment E12 of the present disclosure relates to a compound for use in a method according any one of embodiments E1 to E11 , wherein the compound is used alone or in combination with one or more active substance selected from the group consisting of antivirals, antibiotics, and / or antalgics. An embodiment E13 of the present disclosure relates to a compound for use in a method according to any of embodiments E1 to E12, wherein said treatment is for preventing the occurrence of a lung viral infection, the method comprising administering the compound in a subject that is not infected with a respiratory virus.

[0032] An embodiment E14 of the present disclosure relates to a compound for use in a method according to any of embodiments 1 to 13, wherein the composition is administered intrapulmonary, nasally, orally, enterally, intravenously, intramuscularly and subcutaneously.

[0033] An embodiment E15 of the present disclosure relates to a pharmaceutical composition comprising a compound as defined in any one of embodiments E1 to E3 and a pharmaceutically acceptable support for use in a method as defined in any one of the preceding embodiments.

[0034] Detailed description

[0035] An aspect of the present disclosure relates to a compound as described herein or a pharmaceutically acceptable salt thereof for use in a method of treatment of a viral lung infection and / or of an adverse immune response to a viral lung infection, the method comprising administering to a subject in need thereof an effective amount of compound or pharmaceutically acceptable salt thereof.

[0036] Compounds

[0037] The invention thus relates to a compound of formula (I) wherein

[0038] Ri is selected from C1-6 alkyl, benzene, pyridine, pyrimidine, pyrazine, pyridazine, thiophene, R2, Rs are independently selected from H, NH2, NH(CI-6 alkyl), N( C1-6 alkyl)2, CO2Re, OH, SH, S-S-R7, SeH, Se-Se-R7, halogen, SO3R8, O( Ci-6alkyl), P(O)(OH)2, R3, R4, Re are independently selected from H, Na, K, C1-6 alkyl,

[0039] R7is a C1-6 alkyl optionally substituted by n COOH moiety, n being an integer from 1 to 12,

[0040] Rs is selected from Na and K, for use in a method of treatment of treatment of a viral lung infection and / or of an adverse immune response to a viral lung infection, said method comprising administering to a subject in need thereof an effective amount of compound of formula (I) or of a pharmaceutically acceptable salt thereof.

[0041] In the context of the invention, the term “C1-6 alkyl” is to be understood as Ci alkyl, C2alkyl, C3alkyl, C4 alkyl, C5 alkyl and C& alkyl. The term “C1-6 alkyl” refers to C1-6 linear ( / .e., "straightchain"), branched, or cyclic, saturated hydrocarbon chains, including for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, groups.

[0042] In the context of the invention, the term “halogen” refers to fluorine, chlorine, bromine, iodine. In the context of the disclosure, in the terms “n being an integer from 1 to 12”, the range “1 to 12” is to be understood as covering each integer from 1 and 12 and all the ranges comprised in the range “from 1 to 12”, for examples 2 to 12 or 3 to 12.

[0043] In some embodiments, the compound for use according to the disclosure is a compound of formula (I), wherein said compound is of formula (la), (lb), (Ic), (Id) or (le):

[0044] R2, Rs are independently selected from H, NH2, NH(CI-6 alkyl), N( C1-6 alkyl)2, CO2Rs, OH, SH, S-S-R7, halogen, SO3R8, O( Ci-6alkyl), P(O)(OH)2,

[0045] R3, R4, Re are independently selected from H, Na, K, C1-6 alkyl,

[0046] R7is a C1-6 alkyl optionally substituted by n COOH moiety, n being an integer from 1 to 12, Rs is selected from Na and K.

[0047] In the context of the invention, compounds of formula (Id) can be selected from compounds of formula (Id1 ), (Id2) and (Id3) represented below: wherein R2, R3, R4, R5, Re, R7 and Rs are as previously defined.

[0048] According to a particular embodiment, the compound of the invention of formula (la) can be selected from: wherein R2, R3, R4, R5, Re, R7 and Rs are as previously defined.

[0049] According to a particular embodiment, the compound of the invention of formula (la) can be selected from: wherein

[0050] R2, Rs are independently selected from H, NH2, NH(CI-6 alkyl), N( C1-6 alkyl)2, CO2Rs, OH, SH, S-S-R7, halogen, SO3Rs, O( C1-6 alkyl), P(O)(OH)2, and R2and Rs are not simultaneously H, OH or SH,

[0051] R3, R4, R6are independently selected from H, Na, K, C1-6 alkyl,

[0052] R7is a C1-6 alkyl optionally substituted by n COOH moiety, n being an integer from 1 to 12, Rs is selected from Na and K. According to a particular embodiment, the compound of the invention of formula (la) is not malic acid.

[0053] According to a particular embodiment, the compound of formula (lb) can be selected from: wherein R2, R3, R4, Rs, Re, R7 and Rs are as previously defined.

[0054] According to a particular embodiment, the compound of formula (lb) can be selected from: wherein R2, R3, R4, Rs, Re, R7 and Rs are as previously defined.

[0055] According to a particular embodiment, the compound of formula (Ic) can be selected from wherein R2, R3, R4, Rs, Re, R7 and Rs are as previously defined.

[0056] According to a particular embodiment, the compound of formula (Ic) can be wherein R2, R3, R4, Rs, Re, R7 and Rs are as previously defined.

[0057] According to a particular embodiment, the compound of formula (Id) can be selected from wherein R2, R3, R4, Rs, Re, R7 and Rs are as previously defined.

[0058] According to a particular embodiment, the compound of formula (I) can be of formula (If) wherein R3and R4 are as previously defined, R9is independently selected from H, Na, K, C1-6 alkyl.

[0059] According to a particular embodiment, the compound for use as described herein can be selected from the group consisting of : 5 According to a particular embodiment, the compound for use according to the invention can be selected from the group consisting of:

[0060] The compounds of the present disclosure and their pharmaceutically acceptable salts may contain one or more asymmetric centers, chiral axes and chiral planes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms and may be defined in terms of absolute stereochemistry, such as (R)- or (S)-. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms.

[0061] In addition, the compounds of the present disclosure also may exist in hydrated and anhydrous forms. Hydrates of any of the formulas described herein may thus exist as a monohydrate or in the form of a polyhydrate.

[0062] As used herein, the term “pharmaceutically acceptable salt” is intended to mean base addition salts. Example of pharmaceutically acceptable salts are also described, for example, in Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci. 66, 1 -19 (1977). Pharmaceutically acceptable salts may be synthesized from the parent agent that contains an acidic moiety, by conventional chemical methods. Generally, such salts and are prepared by reacting the free acid forms of these agents with a stoichiometric amount of the appropriate base in water or in an organic solvent, or in a mixture of the two. Likewise, when the parent agent contains a group such as -NH2, the pharmaceutically acceptable salts may be synthesized from the parent agent by conventional chemical methods by reacting the free -NH3+ with an anionic source in a suitable solvent.

[0063] Salts may be prepared in situ, during the final isolation or purification of the compound or by separately reacting a purified compound of the present disclosure with the desired corresponding base, and isolating the salt thus formed. For example, this approach may be implemented with the free acid form of some of the compounds of the present disclosure.

[0064] The pharmaceutically acceptable salt of the compounds of the present disclosure may be selected from the group consisting of organic or inorganic salts.

[0065] For example, the pharmaceutically acceptable salt may include a sodium, potassium, calcium, magnesium, lithium, ammonium, manganese, zinc, iron, olamine, meglumine, lysine, tromethamine, or copper salt, when the compounds are amenable to be such salts. In preferred embodiments, the pharmaceutically acceptable salt of the compounds of the present disclosure may be the sodium, potassium, calcium, magnesium or lithium salt, when the compounds are amenable to be such salts. More preferably the pharmaceutically acceptable salt is sodium, when the compounds are amenable to be such salts.

[0066] For example, the pharmaceutically acceptable salt may include an acetate, benzoate, besylate, bromide, carbonate, citrate, edisylate, estolate, fumarate, gluconate, hippurate, iodide, maleate, mesylate, methylsulfate, napsylate, oxalate, pamoate, phosphate, stearate, succinate, sulfate, tartrate, tosylate, or chloride salt, when the compounds are amenable to be such salts.

[0067] All alcohol, salt and other ionic and non-ionic forms of the compounds described are included when referring to a given compound, where applicable. For example, if a compound is shown as an alcohol herein, the salt forms of the compound are also included, when the compounds are amenable to be such salts. Likewise, if a compound is shown as a salt herein, then the alcohol forms are also included. The same is also applicable to a compound having an aromatic group in one of the substituent groups, where such aromatic group on the substituent group may include a free form of a carboxylic acid. In such case, when the compound is shown as a salt herein, then the carboxylic acid free form is also included. Likewise, when the aromatic group on the substituent group is shown with a free form of a carboxylic acid, then the salt forms of the compound are also included, when the compounds are amenable to be such salts.

[0068] The compound of formula (I) according to the present disclosure can be prepared according to any chemical routes known from a skilled person, such the synthetic routes presented in the examples. It is thus understood that one skilled in the art of organic chemistry can easily synthesize the compound of formula (I) using appropriate starting materials, conventional chemicals reactions, standard and literatures procedures, and experimental conditions to synthesize the compounds of formula (I).

[0069] Compound for use

[0070] As illustrated by examples, the inventors have demonstrated the therapeutic interest of the compounds as described herein. Indeed, the inventors have shown that the compounds according to the present disclosure are useful in a method of treatment of a viral infection and / or an adverse immune response to a viral infection, especially of a lung viral infection such as an IAV infection.

[0071] Lung viral infection

[0072] As used in the present disclosure, the term “lung viral infection” relates to a condition characterized by (i) the proliferation of one or more virus in the lungs of the subject, and / or (ii) one or more adverse immune response associated to or induced by said viral infection in the lungs of the subject. A lung is a specific organ within the respiratory system. Humans typically have two lungs. According to the present disclosure, lung viral infections may affect other organs of the respiratory system selected from the group consisting of the pharynx, the larynx or the tracheobronchial tree (composed of the trachea, the bronchi and the bronchioles).

[0073] A viral infection can cause a spectrum of symptoms, from no obvious symptoms to severe illness. The pathological changes in the lungs due to a viral infection typically include or more of cell damage (i.e. viral replication in lung cells leads to cell death and tissue damage, immune response (i.e. infiltration of immune cells such as lymphocytes, neutrophils, and macrophages to combat the virus), inflammation (i.e. swelling and irritation of the lung tissues), fluid accumulation (i.e. fluid buildup in the alveoli, leading to impaired gas exchange, and mucus production (i.e. increased mucus production, which can block airways and cause breathing difficulties). These pathological changes primarily affect the respiratory system and may result in a decreased or impaired respiratory function in the subject. As it will be described below, viral lung infection may also result in more systemic complications due to an adverse immune response associated to or induced by said viral infection in the lungs of the subject.

[0074] Virus-induced cytopathic effects (CPE)

[0075] As used herein, the expression “virus-induced cytopathic effects” or “viral cytopathic effects” abbreviated “CPEs” refers to the visible structural changes or damage in the cells of the subject that result from the virus taking over the host cell's machinery to replicate and produce new viral particles, often disrupting normal cellular functions and ultimately leading to cell death. These changes can be observed under a microscope and are indicative of the presence and activity of a virus within the cells.

[0076] CPEs manifestations usually include one or more of cell rounding (i.e. the infected cells lose their normal shape and become rounded), cell detachment (i.e. the cells detach from the surface they are growing on), lysis (i.e. the cell membrane ruptures, leading to cell death), formation of viral inclusion bodies (i.e. formation of abnormal structures within the cell, such as aggregates of viral particles or altered host cell organelles), syncytium formation (i.e. infected cells fuse to form large multinucleated cells called syncytia), chromatin margination (i.e. chromatin in the nucleus condenses and is displaced to the edges of the nucleus), and vacuolization (i.e. formation of vacuoles or pockets within the cytoplasm).

[0077] The damage to respiratory epithelial cells, in particular, can impair the function of the respiratory tract and make it more susceptible to secondary bacterial infections. The CPEs can contribute to the pathogenesis and thus to the symptoms of the lung viral infection.

[0078] In some embodiments, the lung viral infection induces or is capable of inducing one or more viral cytopathic effects in the lungs of the subject. Therefore, in some embodiments, the compound for use as described herein is for use in a method of treatment of one or more viral cytopathic effects induced by a lung viral infection.

[0079] Adverse immune response

[0080] As used herein, the expression “adverse immune response”, or “host adverse immune response”, or “subject’s adverse immune response” refers to a syndrome of physiologic, pathologic, and / or biochemical abnormalities triggered by a viral infection. The expression “adverse immune response” refers also to organ dysfunction due to dysregulated host response to infection than can be defined as “sepsis”.

[0081] Clinical manifestations of an adverse immune response to a lung viral infection usually include one or more of abnormal body temperature (typically characterized in human by a body temperature greater than 38°C or lower than 36°C), dyspnea, tachypnea (typically characterized in human by a respiratory rate greater than 20 / min), bronchitis, pneumonia, sepsis-induced organ dysfunction, and acute respiratory distress syndrome (ARDS).

[0082] Biological manifestations usually include one or more of abnormal white blood cell count (typically characterized in human by a WBC count greater than 12000 / mm3or lower than 4000 / mm3or greater than 10% immature bands), excessive release of systemic cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1 ), interleukin-6 (IL-6), interleukin-8 (IL-8), hyper-inflammatory immune response, such as a cytokine storm or cytokine release syndrome, coagulopathy (consumption of coagulation factors, fibrinogen, and platelets), hypoxemia assessed by arterial blood gas analysis (typically characterized by a PaO2 / FiO2 inferior or equal to 300 mmHg). Imaging manifestation usually includes the presence of pulmonary infiltrates on chest radiograph and / or CT scan.

[0083] In some embodiments, the lung viral infection induces or can induce an adverse immune response in the subject. Therefore, in some embodiments, the compound for use as described herein is for use in a method of treatment of an adverse immune response induced by a lung viral infection. In some embodiments, the adverse immune response to the lung viral infection is a hyper-inflammatory immune response, a dyspnea, a tachypnea, a pneumonia in particular an acute pneumonia, an exacerbation of a chronic respiratory disease such as asthma or chronic obstructive pulmonary disease, a sepsis, a septic shock, a cytokine storm or an acute respiratory distress syndrome (ARDS). In some embodiments, the adverse immune response to the lung viral infection is pulmonary hypertension or hypotension.

[0084] In some embodiments, the adverse immune response to the lung viral infection is a multi-organ failure. Multi-organ failure may comprise heart failure, liver failure, lung failure kidney failure, or gastrointestinal (Gl) system failure.

[0085] Immunomodulatory and antiviral properties

[0086] In some embodiments, the compound for use according to the disclosure has immunomodulatory properties and / or antiviral properties, preferably wherein:

[0087] - the immunomodulatory properties include the reduction or inhibition of the inflammation response to the viral lung infection;

[0088] - the antiviral properties include the reduction or inhibition of viral replication.

[0089] Immunomodulatory properties

[0090] In some embodiments, the compound has immunomodulatory properties, preferably has antiinflammatory properties. Accordingly, in some embodiments, the compound is an immunomodulator compound, preferably is an anti-inflammatory compound.

[0091] In the present disclosure, the term “immunomodulatory agent”, “immunomodulatory medicament” or “immunomodulator” refer to a substance that inhibits or reduces one or more adverse immune responses to a lung disease due to a virus in the subject, in particular a hyper- inflammatory immune response to the lung viral infection. The capacity of a substance to reduce an inflammatory response may for example be confirmed by measuring a diminution of the expression of some components of the inflammatory cascade such as IL-6, IL-8 or tumor necrosis factor-alpha (TNF-a) and / or a diminution of the infiltration of immune cells such as lymphocytes, neutrophils and macrophages in the presence of that substance.

[0092] In some embodiments, the immunomodulatory properties of the compound for use according to the disclosure include inhibiting or reducing the lung immune inflammation response triggered by a virus, in particular a respiratory virus.

[0093] Therefore, in some embodiments, the compound for use according to the disclosure treats the lung viral infection as an immunomodulatory medicament, particularly by inhibiting or reducing the lung immune inflammation response triggered by the lung virus infection.

[0094] In some embodiments, the compound for use according to the disclosure is for treating an adverse immune response to a lung virus infection. The adverse immune response typically involves a hyper-inflammatory immune response and is preferably selected from acute exacerbations of a chronic respiratory disease such as asthma or chronic obstructive pulmonary disease, pneumonia, sepsis, septic shock, cytokine storm and acute respiratory distress syndrome. Such adverse immune response may occur in moderate to advanced cases of said lung virus infection, which may be caused by an influenza virus or a coronavirus such as SARS-CoV-2.

[0095] In some embodiments, the compound reduces the concentration of interleukin-6 (IL-6) by at least 50% in an in vitro assay assessing anti-inflammatory activity, wherein human bronchial epithelial cells (e.g. BEAS-2B cells) are infected with influenza A virus (e.g. A / Scotland / 20 / 74, H3N2 strain) and treated with the compound four hours post-infection, IL-6 levels being measured in cell culture supernatants at 20 hours post-infection, and wherein said reduction is preferably observed at a compound concentration of 5 mM or less, preferably 4.5 mM or less, more preferably 4 mM or less, even more preferably 3.5 mM or less, 3 mM or less, 2.5 mM or less, 1 .5 mM or less, 1 mM or less, or most preferably 0.5 mM or less. An in vitro assay for assessing anti-inflammatory activity of the compound is further described in the Examples.

[0096] Antiviral properties

[0097] In some embodiments, the compound for use according to the disclosure has antiviral properties, preferably has antiviral properties. Accordingly, in some embodiments, the compound is an antiviral compound.

[0098] In the present disclosure, the term “antiviral medicament” or “antiviral” refers to a substance that inhibits or reduces virus replication in a subject.

[0099] In some embodiments, the antiviral properties of the compound for use according to the disclosure include inhibition of viral replication.

[0100] In some embodiments, the compound for use according to the disclosure treats a lung viral infection as an antiviral medicament, more particularly by disrupting the life cycle of the respiratory virus.

[0101] In some embodiments, the compound reduces influenza A virus neuraminidase (NA) activity by at least 50% in an in vitro assay, wherein human bronchial epithelial BEAS-2B cells are infected with influenza A virus (e.g. A / Scotland / 20 / 74, H3N2 strain) and treated with the compound four hours post-infection, NA activity being measured in cell culture supernatants at 20 hours post-infection, and wherein said reduction is preferably observed at a compound concentration of 5 mM or less, preferably 4.5 mM or less, more preferably 4 mM or less, even more preferably 3.5 mM or less, 3 mM or less, 2.5 mM or less, 1 .5 mM or less, 1 mM or less, or most preferably 0.5 mM or less. An in vitro assay for assessing antiviral activity of the compound is further described in the Examples.

[0102] In some preferred embodiments, the compound for use according to the disclosure treats the lung viral infection both as an immunomodulatory medicament and as an antiviral medicament.

[0103] In some embodiments, the compound inhibits or reduces both viral replication and virus- induced inflammation. In some embodiments, the compound is an anti-inflammatory and / or antiviral compound-Respiratory virus

[0104] In some embodiments, the viral infection is caused by a respiratory virus.

[0105] In the present disclosure, the term “respiratory virus” refers to a virus having a tropism for the airway cells and in particular for the lungs of the subject, and able to cause an adverse immune response as described herein.

[0106] In some embodiments, the respiratory virus is selected from an influenza virus, a coronavirus, a respiratory syncytial virus, a parainfluenza virus, a metapneumovirus, a rhinovirus, an adenovirus, a varicella-zoster virus, a cytomegalovirus, a paramyxovirus such as a Nipah virus, an enterovirus, and a bocavirus.

[0107] Influenza virus

[0108] In some embodiments, the respiratory virus is an influenza virus.

[0109] In some embodiments, the influenza virus is an Influenza A virus, an Influenza B virus, an Influenza C virus or an Influenza D virus.

[0110] In some embodiments, the influenza A virus is of serotype H1 N1 , H1 N2, H2N2, H2N3, H3N1 , H3N2, H3N8, H5N1 , H5N2, H5N3, H5N6, H5N8, H5N9, H6N1 , H6N2, H7N1 , H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, or H10N7.

[0111] In some embodiments, the influenza virus is an Influenza B virus. In some embodiments, the Influenza B virus is of serotype Victoria or Yamagata.

[0112] In some embodiments, the influenza virus is an influenza virus usually causing human influenza, for example a H1 N1 , H2N2, H3N2, H5N1 , H7N7, H1 N2, H9N2, H7N2, H7N3, or H10N7 influenza virus.

[0113] In some embodiments, the influenza virus is an influenza virus usually causing avian influenza, for example a H5N1 or H7N9 influenza virus.

[0114] In some embodiments, the influenza virus is an influenza virus usually causing swine or pig influenza such as H1 N1 , H1 N2, H2N1 , H3N1 , H3N2, H2N3, or influenza c virus.

[0115] In some embodiments, the influenza virus is an influenza virus usually causing equine influenza such as H7N7 or H3N8 influenza virus.

[0116] In some embodiments, the influenza virus is an influenza virus usually canine influenza such as H3N8 influenza virus.

[0117] In some embodiments, the compound for use according to the disclosure reduces or inhibits both the influenza virus replication and the immune inflammation response to an influenza virus infection.

[0118] Coronavirus

[0119] In some embodiments, the respiratory virus is a coronavirus virus of Orthocoronavirinae subfamily, as a coronavirus.

[0120] In some embodiments the coronavirus is selected from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus (SARS-CoV), or Middle East respiratory syndrome coronavirus (MERS-CoV) or beta-coronavirus.

[0121] In some embodiments the coronavirus is SARS-CoV-2.

[0122] In some embodiments, the compound for use according to the disclosure reduces or inhibits at least the immune inflammation response to the coronavirus infection, and optionally also reduces the immune inflammation response to a coronavirus infection.

[0123] Viral respiratory disease

[0124] In some embodiments, the compound for use according to the disclosure is for use in treating a respiratory viral disease.

[0125] As used in the present disclosure, the term “viral respiratory disease” relates to a condition or disorder that affects the respiratory system.

[0126] In some embodiments, the compound for use according to the disclosure is for use in treating a respiratory viral disease characterized in that it is caused by a particular respiratory virus, especially as respiratory virus as described herein.

[0127] In some embodiments, the compound for use according to the disclosure is for use in treating a respiratory viral disease characterized in that it is caused by a respiratory virus is selected from an influenza virus, a coronavirus, a respiratory syncytial virus, a parainfluenza virus, a metapneumovirus, a rhinovirus, an adenovirus, a varicella-zoster virus, a cytomegalovirus, a paramyxovirus such as a Nipah virus, an enterovirus and a bocavirus.

[0128] In some embodiments, the compound for use according to the disclosure is for use in treating a respiratory viral disease characterized in that it is caused by an influenza virus. Although viral respiratory diseases can be classified according to a causative virus (e.g., influenza), they may also be classified clinically irrespective of the causal agent according to a syndrome (e.g. bronchiolitis, pneumonia, acute respiratory distress syndrome). In the present disclosure, the term “syndrome” refers to recognizable patterns of symptoms and signs that occur together and characterize a particular viral respiratory disease or condition. Thus, a viral respiratory disease may be characterized by a particular syndrome. Specific viruses commonly cause characteristic clinical manifestations (e.g., rhinovirus typically causes the common cold, respiratory syncytial virus (RSV) typically causes bronchiolitis), but can also cause the general symptoms of diseases caused by other viruses. These symptoms can include cough, sore throat, runny or stuffy nose, fever, fatigue, muscle aches, and difficulty breathing in severe cases.

[0129] "Influenza", commonly known as the flu refers to the collection of symptoms and signs associated with an influenza virus infection, primarily influenza A and B viruses. The influenza syndrome typically manifests suddenly and can range from mild to severe, sometimes leading to hospitalization and even death, particularly in high-risk groups such as young children, elderly individuals, pregnant women, and those with underlying health conditions.

[0130] "Influenza encephalitis", or “influenza-associated encephalitis”, refers to a rare yet serious neurological condition that can arise from an influenza virus infection. This complication generally follows a severe infection by specific strains of the influenza virus, particularly influenza A and B, and predominantly affects children and young adults. Clinical characteristics encompass a combination of flu symptoms and central nervous system dysfunctions, in addition to the conventional flu symptoms, there are neurological manifestations such as seizures, alterations in consciousness, diminished cognitive processing, including speech, motor paralysis or sensory loss, unusual or delirious behaviour, and shifts in mental state. The emergence of neurological complications may occur within a span of several days following the initial onset of flu symptoms.

[0131] "Influenza-like illness" (ILI) is a term used to describe a set of symptoms that are similar to those of influenza. These symptoms typically include fever, cough, sore throat, muscle aches, fatigue, and sometimes headache and nasal congestion. ILI can be caused by influenza viruses or various respiratory viruses besides influenza, including respiratory syncytial virus (RSV), adenovirus, rhinovirus, and coronaviruses.

[0132] "Bronchiolitis" refers to a respiratory condition characterized by an inflammation of the bronchioles, the smallest air passages in the lungs. It mainly occurs in infants and young children. Symptoms of bronchiolitis often start with cold-like symptoms such as a runny or stuffy nose, cough, and mild fever. As the illness progresses, symptoms can worsen to include wheezing, difficulty breathing, rapid breathing, and sometimes a decreased appetite or dehydration. It is most commonly caused by a respiratory syncytial virus (RSV) infection but may be caused by other viruses including influenza viruses, parainfluenza viruses, adenoviruses, rhinoviruses, coronaviruses and metapneumoviruses.

[0133] “Bronchitis” refers to a respiratory condition characterized by an inflammation of bronchi, which are the larger airways that branch off from the trachea and lead to the lungs. It can occur in all age groups. Common Symptoms of bronchitis are rapid breathing, wheezing, cough, nasal congestion, difficulty feeding (in infants), and sometimes fever. It is commonly caused by a respiratory syncytial virus (RSV) infection but may be caused by other viruses including influenza viruses, parainfluenza viruses, adenoviruses, rhinoviruses, coronaviruses and metapneumoviruses. “Common cold” refers a viral infection of the upper respiratory tract, primarily caused by rhinoviruses. Other viruses, such as coronaviruses, adenoviruses, and respiratory syncytial virus (RSV), can also cause colds. It is characterized by symptoms such as runny or stuffy nose, sneezing, sore throat, cough, fatigue and fever. It is primarily caused by Rhinoviruses but may be caused by other viruses including influenza viruses, parainfluenza viruses, enteroviruses, adenoviruses, and metapneumoviruses.

[0134] “Croup” refers to a respiratory condition that primarily affects infants and young children, characterized by inflammation and swelling of the upper airway, particularly the larynx (voice box) and trachea (windpipe). It typically presents with a barking cough, hoarseness, and stridor (a high-pitched sound heard during inhalation). It is primarily caused by parainfluenza viruses but may be caused by other viruses including influenza viruses, RSV or adenoviruses.

[0135] In some embodiments, the compound for use according to the disclosure is for use in treating a respiratory viral disease selected from influenza, influenza encephalitis, influenza-like illness, bronchiolitis, bronchitis, common cold, and croup.

[0136] Some viral respiratory diseases are characterized by syndromes arising as an adverse immune response to a viral infection. Such syndromes can include pneumonia (inflammation of the air sacs in one or both lungs), sepsis (widespread inflammation, which can lead to organ dysfunction and failure) or acute respiratory distress syndrome (lungs are unable to provide adequate oxygen to the body's tissues and / or remove carbon dioxide from the bloodstream).

[0137] “Pneumonia” refers to a respiratory condition characterized by inflammation of the air sacs (alveoli) in one or both lungs. The alveoli may fill with fluid or pus, causing symptoms such as cough, fever, chills, and difficulty breathing. Pneumonia can be caused by a variety of infectious agents, including viruses, bacteria and fungi, as well as by inhalation of certain chemicals or irritants. Viral pneumonia is commonly caused by influenza viruses, RSV, adenoviruses and coronaviruses including SARS-CoV-2 but may be caused by other viruses including parainfluenza viruses, enteroviruses, rhinoviruses, metapneumoviruses.

[0138] “Sepsis” refers to a condition characterized by widespread inflammation that may lead to tissue damage and organ failure. Sepsis can be caused by a variety of infectious agents, including viruses, bacteria and fungi. Viral sepsis is commonly caused by influenza viruses, RSV, adenoviruses and coronaviruses including SARS-CoV-2 but may be caused by other viruses including parainfluenza viruses, enteroviruses, rhinoviruses, metapneumoviruses.

[0139] “Acute respiratory distress syndrome” (ARDS) is a respiratory condition characterized by rapid onset of widespread inflammation in the lungs, leading to fluid accumulation in the air sacs (alveoli) and resulting in severe oxygenation impairment and difficulty breathing. ARDS typically occurs as a complication of another underlying illness or injury, such as pneumonia, sepsis, trauma, or inhalation injury. Viral ARDS is commonly caused by influenza viruses, RSV, adenoviruses and coronaviruses including SARS-CoV-2 but may be caused by other viruses including parainfluenza viruses, enteroviruses, rhinoviruses, metapneumoviruses.

[0140] In some embodiments, the compound for use according to the disclosure is for use in treating a respiratory viral disease selected from pneumonia, sepsis, or acute respiratory distress syndrome (ARDS).

[0141] Some viral respiratory syndromes and their viral cause are illustrated below:

[0142] In some embodiments, the compound for use according to the disclosure is for use in treating a respiratory viral disease selected from influenza, influenza encephalitis, influenzalike illness, bronchiolitis, bronchitis, common cold, croup, pneumonia, sepsis, and acute respiratory distress syndrome (ARDS).

[0143] Method of treatment

[0144] As used in this document, the term “treatment” or “therapy” refers to any action which makes it possible to reduce or suppress the symptoms associated with a pathological condition. It comprises both a curative treatment and a prophylactic treatment for a disease. A curative treatment is defined by a treatment resulting in a cure or a treatment which relieves, improves and / or eliminates, reduces and / or stabilizes the symptoms of a disease or the suffering that it causes. The term “curative treatment" may refer to one or more of (1 ) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease or reducing or alleviating one or more symptoms of the disease. In particular, with reference to the treatment of a lung viral infection, the term “curative treatment” may refer to the inhibition of the viral infection and / or of the adverse immune reaction associated to said viral infection. A prophylactic treatment comprises both a treatment resulting in the prevention of a disease and a treatment which reduces and / or delays the incidence of a disease or the risk of it occurring. The terms “improve” and “reduce” include, but do not require complete recovery or complete prevention. The term “prophylactic treatment" may refer to one or more of preventing the disease; for example, preventing a disease, condition or disorder in an individual who is at risk of experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., preventing the development of the pathology and / or symptomatology); and (2) reducing and / or delaying the incidence of a disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease or reducing or alleviating one or more symptoms of the disease.

[0145] In the context of the present disclosure, the term “treatment” may refer to the curative or prophylactic treatment of viral lung infection and / or of an adverse immune response to a lung viral infection as described herein. In particular, with reference to the method of the present disclosure, the term “prophylactic treatment” may refer to the prevention of the viral infection and / or of the adverse immune reaction to said viral infection. Thus, the term “treatment” may refer to one or more of:

[0146] - the curative treatment of a viral infection,

[0147] - the curative treatment of an adverse immune response to a viral infection,

[0148] - the prophylactic treatment of a viral infection, and

[0149] - the prophylactic treatment of an adverse immune response to a viral infection.

[0150] The term “treatment” may also refer to the curative or prophylactic treatment of a viral respiratory diseases as described herein.

[0151] The disclosure also provides the use of a compound as described herein optionally in association with a pharmaceutically acceptable support and / or one or more active substance as described herein for the manufacture of a medicament for the treatment of a viral lung infection and / or of an adverse immune response to said viral lung infection, as described herein.

[0152] In another embodiment, the present disclosure provides a method of treatment of a viral lung infection and / or of an adverse immune response associated to a viral lung infection, the method comprising administering to a subject in need thereof an effective amount of compound for use according to the disclosure optionally in association with a pharmaceutically acceptable support and / or one or more active substance as described herein.

[0153] Dose

[0154] The compound for use according to the disclosure is administered to the patient at an effective dose. The term “effective” dose” or “therapeutically effective dose” as used herein refers to the amount required to observe a curative or prophylactic activity on the lung infection, and for example an amount required to observe an inhibition or a reduction of viral infection and / or to the adverse immune reaction to the lung viral infection. The amount of compound to be administered and the duration of the treatment are evaluated by those skilled in the art according to criteria such as the physiological condition of the subject to be treated, the nature of the lung infection or lung hyperinflammation response to be treated, and the administration route used. The compound for use according to the disclosure can be administered in the form of a single dose or multiple doses.

[0155] In some embodiments, the compound for use according to the present disclosure is administered to said subject in a therapeutically effective dose, for example at a dose to reach a concentration of about 0.3 to about 10 mM at the site of treatment (e.g. the respiratory tract). Nevertheless, this exemplary dose can vary within wide limits and is to be suited to the individual conditions in each individual case.

[0156] Patient selection

[0157] The subject to be treated, or patient, is an animal, preferably a mammal.

[0158] According to one preferred embodiment, the subject to be treated is a human, preferably an adult. In some embodiments, the subject is an aged human patient, in particular being more than 50, 60, 70, 80, 90 years old, more particularly being more than 65 years old. In some embodiments, the subject is a child, in particular a child being less than 2, 5, 7 or 10 years old.

[0159] In some embodiments, the subject to be treated is a subject vulnerable to lung viral infection. As used herein “vulnerable” denotes individuals that may encounter difficulty in protecting themselves are therefore at greater risk to suffers disproportionately from a lung viral infection and its complications. Subjects vulnerable to lung viral infection include but are not limited to aged patients, in particular aged patents of 65 years old or more, children in particular children of 2 years or less, and pregnant women.

[0160] According to an embodiment, the subject to be treated is an animal other than human, preferably a domestic animal selected from the group consisting of a bird, a dog, a cat, a horse, a cow, a sheep, a pig and a non-human primate.

[0161] The domestic bird is for example a chicken, a duck, a goose or a turkey.

[0162] In some embodiments, the subject is an animal, preferably a human or a domestic bird.

[0163] The subject to be treated

[0164] Subject to be treated

[0165] The method of the present disclosure may be applied to a subject prior or after a viral lung infection, prior or after the appearance of an adverse immune response to said viral infection.

[0166] The method of the present disclosure can thus be applied to a subject that is infected or uninfected, as a curative and / or prophylactic treatment, at different levels of severity of the viral infection as described herein.

[0167] In some embodiments, the subject is at risk of developing an adverse immune response to the viral lung infection, for example to develop a pneumonia.

[0168] In some embodiments, the subject at risk of developing an adverse immune response to the viral lung infection is an aged human patient, preferably a human patient being more than 50, 60, 70, 80, 90 years old, in particular a human patient of 65 years old or more. It may also be a child in particular child of 2 years or less, or a pregnant woman.

[0169] The subject is infected

[0170] In some embodiments, the method of the disclosure is applied to a subject infected, i.e. having a viral lung infection. In some embodiments, the method of the disclosure is applied to treat the viral lung infection.

[0171] In some embodiments, the method of the disclosure is applied for the curative treatment of a viral lung infection.

[0172] In some embodiments, the method of the disclosure is applied to prevent the subject from developing an adverse immune response to the viral lung infection.

[0173] In some embodiments, the method of the disclosure is applied to prevent the subject from developing a hyper-inflammatory immune response, a dyspnea, a tachypnea, a pneumonia in particular an acute pneumonia, an exacerbation of a chronic respiratory disease such as asthma or chronic obstructive pulmonary disease, a sepsis, a septic shock, a cytokine storm or an acute respiratory distress syndrome (ARDS).

[0174] In some embodiments, the method of the disclosure is applied to prevent the lung viral infection from escalating to an adverse immune response.

[0175] In some embodiments, the method of the disclosure is applied for the prophylactic treatment of an adverse immune response to a lung viral infection.

[0176] In some embodiments, the method of the disclosure is applied for the curative treatment of a lung viral infection and for the prophylactic treatment of an adverse immune response to the lung viral infection.

[0177] The subject is infected and presents an adverse immune reaction to the infection

[0178] In some embodiments, the method of the disclosure is applied to treat an adverse immune response caused by a viral lung infection.

[0179] In some embodiments, the method of the disclosure is applied for the curative treatment of an adverse immune response to a lung viral infection.

[0180] In some embodiments, the method of the disclosure is applied for the curative treatment of a viral infection and for the curative treatment of an adverse immune response to the lung viral infection.

[0181] The subject is uninfected.

[0182] In some embodiments, the method of the disclosure is applied to a subject uninfected with a viral infection.

[0183] In some embodiments, the method of the disclosure is applied for prophylactic treatment of a lung viral infection and / or an adverse immune response to the viral lung infection.

[0184] Severity / stage of the viral infection

[0185] The method can be applied at various stages of the viral lung infection.

[0186] The inventors have shown for some compounds according to the disclosure that, surprisingly, in a murine model of IAV infection, these compounds were effective even when administered at a distance from the infection (2 or even to 4 days post-infection). This result strongly suggests that these compounds can treat an advanced stage lung infection. As used herein, “advanced stage lung infection”, refers to patient with lung infection that needs oxygen therapy. This is particularly advantageous because current antiviral treatments, such as Tamiflu®, are ineffective alone on advanced IAV infections.

[0187] In some embodiments, the treatment according to the disclosure is for treating a subject at an advanced stage of the lung viral infection. In these embodiments, the compound for use according to the disclosure is preferably administered to the subject at between 2 to 14 days, preferably at between 4 to 14 days post infection, preferably at between 5 to 1 1 days post infection, more preferably at 7 to 1 1 days post infection. In some embodiments, the compound for use according to the disclosure is preferably administered to the subject at between 4 to 11 days post infection, more preferably 4 to 7 days post infection.

[0188] In some other embodiments, the treatment according to the disclosure is for treating a subject at an early stage of the lung infection.

[0189] In these embodiments, the compound for use according to the disclosure is preferably administered to the subject immediately, one hour, 6 hours, 12 hours, 1 day, 2 days, 3 days post infection, between 8 to 24 hours post infection, more preferably between 10 to 20 hours post infection, even more preferably at 12 to 16 hours post infection.

[0190] In some embodiments, the method according to the disclosure is applied for preventing a lung viral infection from escalating to an adverse immune response associated to a viral lung infection in a subject that is suffering from a lung viral infection.

[0191] Without wanting to be bound by any theory, the inventors believe that the compound for use according to the disclosure are probably most effective when given as soon as possible. Yet, as mentioned above the inventors have found that quite surprisingly, some of the compounds for use as described therein are still effective 4 days after infection, which, from a practical and / or clinical point of view, is a significant advantage over the existing antiviral treatments such as Tamiflu® (oseltamivir).

[0192] The method of the present disclosure can be applied to subjects at various stages of the viral infection, i.e. to subjects presenting a variety of severity of viral lung infection and / or adverse immune response to lung viral infection.

[0193] The severity of the subject state may be assessed by a score according to the following ordinal scale where increasing numbers denote increased severity:

[0194] In some embodiments, the subject has a severity assessed as uninfected / ambulatory.

[0195] In some embodiments, the subject has a severity assessed as hospitalized but without ventilatory support.

[0196] In some embodiments, the subject has a severity assessed as hospitalized with ventilatory support.

[0197] Combination therapy

[0198] The compound for use according to the disclosure according to the disclosure can be used as a sole active ingredient or in combination with one or more active substances. The compound for use according to the disclosure and said active substance(s) can be administered simultaneously or sequentially.

[0199] In the present disclosure, the term “administering” means administration of a sole therapeutic agent or in combination with another therapeutic agent.

[0200] According to one embodiment, the compound for use according to the disclosure is used in combination with one or more active substance selected from the group consisting of antivirals, antibiotics, and / or antalgics.

[0201] In some embodiments, the compound for use according to the disclosure is used in combination with one or more antivirals, in particular antivirals of standard therapy of respiratory system viral infections, such as a neuramidase inhibitor (e.g. oseltamivir (Tamiflu®), zanamivir (Relenza®), peramivir (Rapivab®), favipiravir, remdesivir, ribavirin, interferon alpha 2a or 2b, molnupiravir, sotrovimab, casirivimab / imdevimab, baloxavir marboxil (Xofluza®)).

[0202] In some embodiments, the compound for use according to the disclosure is used in combination with one or more antibiotics used in the treatment of bacterial co-infection, in particular antibiotics of standard antibiotherapy such as penicillins, cephalosporins, fluoroquinolones, aminoglycosides, glycopeptides, carbapenems, and macrolides.

[0203] In some embodiments, the compound for use according to the disclosure is used in combination with one or more antalgics such as acetaminophen (paracetamol), nefopam, tramadol, and opioids.

[0204] Routes of Administration

[0205] The compound for use according to the disclosure may be administered via any known administration route, including intrapulmonary, systemically (parenterally, intravenously, etc.), orally, rectally, topically or subcutaneously.

[0206] In some preferred embodiments, the compound for use according to the disclosure is administered intrapulmonary, nasally, orally, enterally, intravenously, intramuscularly and subcutaneously.

[0207] In some preferred embodiments, the compound for use according to the disclosure is administered intrapulmonary. As used herein, “intrapulmonary”, refers to an administration route allowing to deliver the compound for use according to the disclosure to the lungs and / or bronchi, where it particularly concentrates at the alveolar and / or bronchial epithelium.

[0208] In some embodiments, the compound for use according to the disclosure may be administered as an aerosol of a powder or aqueous solution or aqueous suspension, in particular using a nebulizer or a dry powder inhaler.

[0209] In some embodiments, the compound for use according to the disclosure is administered as an aerosol of a powder or aqueous solution or aqueous suspension in subject spontaneously breathing or receiving supplemental oxygen (including high oxygen devices) or being assisted by mechanical ventilation (non-invasive or invasive).

[0210] The term “aerosol”, as used in the present disclosure, refers to a dispersion of solid particles or liquid droplets in a gas adapted for targeting the lower airway passages, and preferably the lungs. A nebulizer is defined as a device capable of aerosolizing a liquid material (solution or dispersion) in the form of inhalable liquid droplets. The nebulizer allows the administration of said composition by means of a mask or a tip disposed on the mouth and / or the nose of the subject.

[0211] Administration regimen

[0212] In some embodiments, the compound for use according to the disclosure and optionally the one or more additional active substance(s) as described herein is or are administered as a single dose, or in a fractionated dose regimen, simultaneously, separately, or sequentially.

[0213] In some embodiments, the compound for use according to the disclosure and optionally the one or more additional active substance(s) as described herein is or are administered to the subject in a fractionated dose regimen.

[0214] In some embodiments, the fractionated dose regimen as described herein comprises 2 to 10 fractionated doses.

[0215] In a preferred embodiment, the fractionated dose regimen as described herein is administered once daily or once every two days.

[0216] In an embodiment, the fractionated doses as described herein are administered with a time lapse between two fractionated doses comprised between 4h and 48h, preferably between 4h and 12h, more preferably between 4h and 10h, for example with a time lapse of 6 hours.

[0217] Pharmaceutical composition

[0218] When employed as pharmaceutical, the compound for use according to the disclosure can be administered in the form of pharmaceutical composition.

[0219] The pharmaceutical composition for use according to the disclosure typically comprise the compound and a pharmaceutically acceptable support, for use as described herein.

[0220] In the context of the disclosure, the term “pharmaceutically acceptable support denotes substances such as excipients, carriers, adjuvants, buffers or the like which are conventionally used, in combination with the active ingredient(s), for the preparation of a medicament. The choice of such supports depends essentially on the route of administration envisaged. Pharmaceutically acceptable supports include diluents (fillers, bulking agents, e.g. lactose, microcrystalline cellulose), disintegrants (e.g. sodium starch glycolate, croscarmellose sodium), binders (e.g. PVP, HPMC), lubricants (e.g. magnesium stearate), glidants (e.g. colloidal SiC>2), solvents / co-solvents (e.g. aqueous vehicle, Propylene glycol, glycerol), buffering agents (e.g. citrate, gluconates, lactates), preservatives (e.g. Na benzoate, parabens (Me, Pr and Bu), BKC), anti -oxidants (e.g. BHT, BHA, Ascorbic acid), wetting agents (e.g. polysorbates, sorbitan esters), thickening agents (e.g. methylcellulose or hydroxyethylcellulose), sweetening agents (e.g. sorbitol, saccharin, aspartame, acesulfame), humectants (e.g. propylene, glycol, glycerol, sorbitol). Other suitable pharmaceutically acceptable supports are inter alia described in Remington’s Pharmaceutical Sciences, 15thEd., Mack Publishing Co., New Jersey (1991 ) and Bauer et ak, Pharmazeutische Technologic, 5thEd., Govi-Verlag Frankfurt (1997). The person skilled in the art knows will readily be able to choose suitable pharmaceutically acceptable supports, depending, e.g., on the formulation and administration route of the pharmaceutical composition.

[0221] In some embodiments, the compound for use according to the disclosure may be in encapsulated form, by being, for example, introduced into microspheres or microcapsules which are reservoirs consisting of a core of active ingredient Surrounded by a membrane of coating material. The polymers forming the coating material may be of natural origin (gelatin, chitosan, etc.), semisynthetic origin (cellulose derivatives, etc.) or synthetic origin, such as the lactic and glycolic acid copolymers commonly used. The compounds of the disclosure may also be encapsulated in polymers such as those mentioned above in the form of a film. The compounds of the disclosure may also be encapsulated in nanoparticles, which are colloidal systems of which the size is between 10 and 1000 nm, based on biodegradable polymers, or on lipids capable of retaining one or more active molecules by sequestration and / or adsorption.

[0222] The pharmaceutical composition according to the disclosure preferably comprises an amount of compound for use according to the disclosure of between 5 pg and 1000 mg, preferably between 1 and 500 mg, preferably between 5 and 100 mg.

[0223] The ratio between the amounts by weight of compound according to the disclosure and of pharmaceutically accept able support may be between 5 / 95 and 95 / 5, preferably between 20 / 80 and 80 / 20.

[0224] The pharmaceutical composition according to the disclosure may for example be formulated as a tablet, capsule, granule, powder, sachet, reconstitutable powder, dry powder inhaler and / or chewable. Such solid formulations may comprise excipients and other ingredients in suitable amounts. Such solid formulations may contain e.g. cellulose, cellulose microcrystalline, polyvidone, magnesium stearate and the like.

[0225] In some preferred embodiments, the pharmaceutical composition is for inhalation. In this case, the dosage can preferably be reduced because of the application of the drug directly to the site of action, i.e. the lungs.

[0226] The present disclosure also relates to a method for treating a lung infection, comprising the administration, to a subject, of an effective amount of compound for use according to the disclosure and / or of a pharmaceutical composition containing the same.

[0227] A subject of the present disclosure is also the use of compound for use according to the disclosure in the context of the preparation of a pharmaceutical composition intended for the treatment of a lung infection.

[0228] Other aspects and advantages of the present disclosure will emerge upon reading the examples which follow, which should be considered to be non-limiting illustrations.

[0229] Legends of the figures

[0230] Figure 1. Linear and cyclic chemical structures evaluated for antiviral activity

[0231] Figure 1 represents examples of linear (series 1 ) and cyclic (series 2) compounds which have been tested. Figure 2. Epithelial tolerance of tested compounds.

[0232] Human bronchial epithelial BEAS-2B cells were treated with various concentrations (in mM) of molecules from Series 1 (Figure 2a) or Series 2 (Figure 2b) for 16 hours. Epithelial tolerance was assessed using the MTS assay. The data are presented as the mean ± SEM from at least two independent experiments.

[0233] Figure 3. Inhibition of viral replication and inflammation by selected compounds

[0234] Among 33 selected compounds, eight drastically inhibit both viral replication and inflammation. Bronchial epithelial BEAS-2B cells were infected with influenza A virus (IAV; A / Scotland / 20 / 74, H3N2) at MOI=1 , or not (MOCK), for 4h and then treated with different concentrations of the selected molecules from Series 1 (Figure 3a, Figure 3b) or Series 2 (Figure 3c, Figure 3d) or Medium (0) for 16 hours. (Figure 3a and Figure 3c) The production of viral particles was assessed by neuraminidase activity assay. (Figure 3b and Figure 3d) Production of human interleukin-6 (h I L6) in cell supernatant was measured by ELISA. All data are presented as the mean ± SEM and are cumulative from a minimum of 2 independent experiments.

[0235] Figure 4. Compounds S1 , S5, S10, S11 and AMH269 prevent mortality in a preclinical animal model of influenza.

[0236] (Figure 4a) 7-week-old female C57BI / 6 mice were infected intranasally with 100 pfu of A / Scotland / 20 / 74 (H3N2) virus (IAV) and treated or not with 75mM of S1 , S5, S7, S10 or S1 1 , or 20mg / kg of Oseltamivir (Osel) 2 days post-infection (by the intranasal route). Animal survival was monitored daily. (Figure 4b) 7-week-old female C57BI / 6 mice were infected intranasally with 100 pfu of A / Scotland / 20 / 74 (H3N2) virus (IAV) and treated or not with 75mM of S1 , S10, S11 or AHM269 at 4 and 5 days post-infection (by the intranasal route). Animal survival was monitored daily. All data are represented as the mean ± SEM and are cumulative of 2 (Figure 4a) or 3 (Figure 4b) independent experiments, with n indicating the number of individual animals. Statistical analysis was performed using the Log-rank (Mantel-Cox) test. *p < 0.05, **p < 0.005, ***p < 0.0005, ****p < 0.0001 .

[0237] Figure 5. Compounds CS17 and AMH269 prevent mortality in a preclinical animal model of influenza.

[0238] (Figure 5a) 7-week-old female C57BI / 6 mice were infected intranasally with 100 pfu of A / Scotland / 20 / 74 (H3N2) virus (IAV) and treated or not with 75mM of CS17 or AHM269 2 days post-infection (by the intranasal route). Animal survival was monitored daily. (Figure 5b) 7-week- old female C57BI / 6 mice were infected intranasally with 100 pfu of A / Scotland / 20 / 74 (H3N2) virus (IAV) and treated or not with 75mM of AHM269 at 4 and 5 days post-infection (by the intranasal route). Animal survival was monitored daily. All data are represented as the mean ± SEM and are representative of 1 (Figure 5a, CS17), 3 (Figure 5a, AHM269 and PBS), or 2 (Figure 5b) independent experiments, with n indicating the number of individual animals. Statistical analysis was performed using the Log-rank (Mantel-Cox) test. *p < 0.05, **p < 0.005, ***p < 0.0005, ****p < 0.0001.

[0239] EXAMPLES

[0240] Example 1 : Compounds for the treatment of influenza infection.

[0241] Abstract

[0242] Influenza remains a major global health threat, annually claiming approximately 500,000 lives worldwide and imposing a considerable socioeconomic burden. Current anti-influenza strategies often have suboptimal efficacy. Given the complex nature of influenza pathophysiology, which involves both cytopathic viral effects and excessive inflammatory responses, there is a growing interest in developing host-directed therapies for more effective interventions. In this context, the inventors evaluated novel synthetic compounds for their potential to inhibit influenza virus replication and modulate inflammation. Several compounds demonstrated both antiviral and anti-inflammatory activities in vitro. Furthermore, selected compounds provided significant protection in murine models of lethal influenza infection within a therapeutically relevant timeframe.

[0243] Introduction

[0244] Influenza A virus (IAV) has consistently caused significant morbidity and mortality since the 1918 pandemic, prompting extensive investigations into therapeutic strategies. Current anti- IAV approaches, such as vaccination and antivirals, exhibit suboptimal effectiveness. The short duration of vaccine-induced immunity and the antigenic drift of influenza viruses compromise host protection. Additionally, skepticism persists regarding the efficacy of approved anti-influenza drugs like the neuraminidase inhibitor oseltamivir (Tamiflu®). Consequently, innovative strategies are crucial for improving influenza virus treatments.

[0245] The pathophysiology of influenza-related pneumonia stems from both viral pathogenicity and the host immune response. While a robust immune response is essential for viral clearance, excessive cellular recruitment and release of cytotoxic molecules lead to lung hyperinflammation, resulting in tissue damage, morbidity, and death.

[0246] Recent discoveries in metabolic reprogramming of immune cells have opened new therapeutic avenues for modulating immune responses. Metabolism is fundamental to all biological functions, and the integration of metabolism with immunity, known as immunometabolism, is at the forefront of immunology research. Our previous studies using mass spectrometry and nuclear magnetic resonance demonstrated significant alterations in metabolite concentrations in the lungs of mice and humans infected with IAV. Metabolites, which are small molecules typically under 1 ,000 Daltons, include sugars, amino acids, nucleotides, and lipids.

[0247] Building on this finding, the inventors studied a series of compounds, selecting 37 (10 linear and 27 cyclic molecules) for their anti-influenza activity. Given that influenza pathophysiology involves both cytopathic viral effects and excessive inflammatory responses, they also examined the anti-inflammatory properties of these compounds.

[0248] Compounds — S1 , S5, S10, S1 1 , and AHM269 — demonstrated a dual effect: inhibition of influenza virus replication and anti-inflammatory properties potent enough to disrupt the inflammatory cascades during influenza. Importantly, in vivo experiments confirmed the efficacy of these molecules in protecting hosts from severe influenza pneumonia, even when administered at a late stage of infection, where conventional treatment with oseltamivir proved ineffective.

[0249] 1.1 / Material and methods

[0250] Chemistry:

[0251] The commercially available compounds S and CS are purchased from suppliers (CS4, CS6, CS11 , and CS 17 were purchased from Acros Organics, CS5, CSCS8, CS9, CS13 and CS16 were purchased from TCI, CS7, CS10, CS12 and CS14 were purchased from Sigma Aldrich, CS3 was purchased from Lancaster, CS18 was purchased from Alfa Aesar and CS19 was purchased from BLD pham).

[0252] The compound labeled AHM are prepared according to the literature.

[0253] Protocol of the preparation of AHM10:

[0015]

[0254] A round bottom flask with a condenser and a Dean-Stark trap was charged with a solution of 3,4,5-trimethoxybenzoic acid (300 mg, 1.41 mmol) and sulphiric acid in Methanol (10 mL) and Toluene (5mL). the mixture was stirred at 1 10 °C for two hours. After cooling at room temperature, the crude was extracted with DCM (50 mL) and washed with water (40 mL) and brine (40 mL), dried over MgSO4 and purified by flash chromatography over silica gel (DCM, 100%). The desired product was obtained as a white solid in 91% yield.

[0255] Protocol of the preparation of AHM11 :

[0016] A round bottom flask with a condenser and a Dean-Stark trap was charged with a solution of benzene-1 ,3,5-tricarboxylic acid S1 (300 mg, 1.42 mmol) and sulphiric acid in Methanol (10 mL) and Toluene (5mL). the mixture was stirred at 1 10 °C for two hours. After cooling at room temperature, the crude was extracted with DCM (50 mL) and washed with water (40 mL) and brine (40 mL), dried over MgSO4 and purified by flash chromatography over silica gel (DCM, 100%). The desired product was obtained as a white solid in 93% yield.

[0256] Protocol of the preparation of AHM74: To 1 g of trimesic acid S1 (4.75 mmol) was added 14.26 mL of a 1 mM aqueous solution of NaOH (14,276 mmol). The mixture was stirred for 1 hour. The solvent was lyophilized and the desired product was obtained as a white powder in a quantitative yield.

[0257] Protocol of the preparation of AHM75:

[0258] To 100 mg of Benzene-1 ,3,5-triacetic acid (0.396 mmol) was added 1.19 mL of a 1 mM aqueous solution of NaOH (1.19 mmol). The mixture was stirred for 1 hour. The solvent was lyophilized and the desired product was obtained as a white powder in a quantitative yield.

[0259] Protocol of the preparation of AHM76:

[0260] To 1 g of 3,4-pyridinedicarboxylic acid (2.991 mmol) was added 6 mL of a 1 mM aqueous solution of NaOH (6 mmol). The mixture was stirred for 1 hour. The solvent was lyophilized and the desired product was obtained as a white powder in a quantitative yield.

[0261] Protocol of the preparation of AHM77:

[0262] To 500 mg of 2,6-pyridinedicarboxylic acid (1 .495 mmol) was added 6 mL of a 1 mM aqueous solution of NaOH (6 mmol). The mixture was stirred for 1 hour. The solvent was lyophilized and the desired product was obtained as a white powder in a quantitative yield.

[0263] Protocol of the preparation of disulfide AHM269:

[0017]

[0264] To 8N aqueous solution of NaOH was added gradually mercaptosuccinic acid (1g, 6.6 mmol) at 0°C, then 30% H2O2 (0.55 mL) was added dropwise to the solution at room temperature. The reaction mixture was stirred at rt for 3 hours and subsequently acidified to pH by adding 20% aqueous H2SO4 (2 mL). The reaction mixture was extracted with Et20 and the extract was then dried and evaporated to give the desired compound AHM269 as a white solid in 93% yield.

[0265] Protocol of the preparation of AHM83:

[0018]

[0266] A round-bottom flask was charged with dimethyl 5-iodoisophthalate (300 mg, 0.037 mmol), acetonitrile (5 mL), diethylphosphite (140 pL, 1 .08 mmol), and diisopropylethylamine (160 mg, 2.27 mmol). The flask was flushed with argon for 15 min, after which palladium acetate (3 mg, 0.013 mmol) and 1 ,1 '-bis(diphenylphosphine)ferrocene (dppf, 5 mg, 0.009 mmol) were added. The reaction mixture was stirred and heated in an oil bath at 90 °C for 24 h under constant flow of argon. After cooling to room temperature the mixture was evaporated to dryness in vacuo, and the remaining residue was purified by column chromatography. The obtained compound was then included in a saponification in water using hydrochloric acid at reflux overnight. After evaporating to dryness, the desired compound was obtained as a white solid in 65% yield over two steps.

[0267] Biology:

[0268] Viruses. Mouse adapted-influenza A / Scotland / 20 / 74 (H3N2) was generously given by Pr. Sylvie van der Werf’s team (Pasteur Institute, Paris, France).

[0269] Cell culture. In vitro experiments were performed using human bronchial epithelial BEAS-2B cells, cultured in F-12K Medium supplemented with 10% FBS and 100 U / mL penicillin, 100 pg / mL streptomycin. All cells were mycoplasma-free. BEAS-2B cells were infected in medium without FBS for 4 hours with IAV Scotland at MOI=1 . Four hours after the challenge, cells were washed with PBS and incubated for 4 h or 16 h with different concentrations of candidate compounds. Neuraminidase (NA) assay. The assay measures the release of a 4-methylumbelliferone fluorescent product from the 2'-(4-Methylumbelliferyl)-a-D-N-acetylneuraminic acid sodium salt hydrate (MU-NANA) substrate. 67 pL of cell supernatant was incubated with 33 pL of MU- NANA (50 pM) in black 96-well micro-plates. Fluorescence was immediately measured in a kinetic assay over 1 h at Ex = 355 nm and Em = 460 nm.

[0270] ELISA. Cells supernatants were centrifuged 5 min at 500 g and supernatants were stored at - 80°C. DuoSet ELISA (Human IL-6) was performed according to the manufacturer’s (R&D Systems) instructions.

[0271] Animal infection and treatment. 7-week-old female C57BI / 6 mice were challenged intranasally with 100 pfu of A / Scotland / 20 / 74 (H3N2) IAV, and treated or not with 75mM of S1 , S5, S7, S10, S11 and AHM269 or 20mg / kg of oseltamivir at different time points. Survival was monitored daily. All animal experimentations were performed according to the national governmental guidelines and were approved by our local and national ethics committee (CEEA.19, #201604071220401 -4885).

[0272] Statistical analysis. Analyses were performed using Graph Pad Prism software. All statistical tests were based on raw data and results are expressed as mean ± SEM. The type of statistical test and number of replicates (n) are specified in figure legends. *p < 0.05, **p < 0.005, ***p < 0.0005, ****p < 0.0001 . For in vitro experiments, n = number of independent experiments; for in vivo experiments, n = number of individual animals.

[0273] 1.2 / Results

[0274] In silico and in vitro study of candidate compounds

[0275] To identify "druggable" candidates for pre-clinical trials, we aimed to test a series of compounds that are either (i) commercially available or (ii) already reported in the literature.

[0276] In total, 37 compounds (Series 1 - linear molecules, and Series 2 - cyclic molecules) were selected and / or synthesized as candidate compounds and are presented in Figure 1 .

[0277] In vitro assessment of epithelial tolerance of the candidate compounds.

[0278] Given that the antiviral properties of these molecules would be tested on epithelial cells, we first assessed their tolerance on in vitro human bronchial epithelial BEAS-2B cells.

[0279] For each compound, the maximum non-toxic concentration was identified using MTS viability assays.

[0280] The results are presented on Figure 2.

[0281] In vitro assessment of the anti-viral and anti-inflammatory properties of the candidate compounds.

[0282] Assessment of the anti-viral properties. To this aim, human bronchial epithelial BEAS-2B cells were infected with IAV (A / Scotland / 20 / 74, H3N2 strain) and treated with the candidate molecules 4 hours post-infection (p.i.) (Figure 3). To estimate the release of new virions, we measured IAV neuraminidase (NA) activity in cell supernatants at 20 hours post-infection.

[0283] Assessment of the anti- inflammatory properties. Additionally, we measured the production of interleukin-6 (IL-6), a pro-inflammatory cytokine significantly involved in the immune response to influenza and associated with severe inflammatory responses known as "cytokine storms."

[0284] Due to variations in resuspension techniques, we could not test the same concentration ranges for all molecules. However, all tested concentrations were within the well-tolerated range as previously demonstrated (Figure 2).

[0285] The results are presented in Figure 3. \Ne observed that compounds S1 , S5, S7, S10, S11 , AHM269, CS18, CS15, CS19, CS4, CS10, CS13, CS1 , S17, AHM77, AHM33, and AHM11 reduced NA activity by at least 50% (Figure 3a and Figure 3c). Among them S1 , S5, S7, S10, S11 , AHM269, S17, and AHM11 also reduced IL-6 production by at least 50%, indicating their dual anti-viral and antiinflammatory properties (Figure 3b and Figure 3d).

[0286] Compounds S1 , S5, S10, S11 and AMH269 protect mice from IAV pneumonia.

[0287] We previously identified, in vitro, compounds that were both anti-viral and anti-inflammatory; the compounds were tested thereafter.

[0288] Because the pathophysiology of influenza infection is obviously more complex than one viral read-out and an isolated value of cytokine, it was critical to confirm the relevance of these observations in more complex in vivo models. We infected mice with 100 pfu of IAV and observed 100% of mortality, without intervention.

[0289] To assess the efficacy of the molecules, we defined a straightforward primary outcome measure: animal survival. To mimic the time gap between symptom onset and seeking treatment in humans, we delayed dosing for at least two days.

[0290] The results are presented on Figure 4.

[0291] With this experimental setup, the administration of the approved anti-influenza drug oseltamivir was ineffective in protecting the mice (Figure 4a). Remarkably, administration of S5, S10, S1 1 , and S1 significantly increased mouse survival rates to 50%, 80%, 81%, and 88%, respectively.

[0292] Notably, S7 failed to protect the animals, and AMH269 was not tested in this study.

[0293] Because the average symptom-to-hospitalization time for severe influenza infection in human is 4 days

[0014] , we postponed the treatment until day 4 post-infection and administered second dose of compounds on day 5 post-infection to better simulate clinical practice. S1 , S10, S1 1 and AHM269 demonstrated significant efficacy in treating lAV-infected mice, resulting in a remarkable increase in the survival rate from 0% (control group) to approximately 12, 28, 33 and 80% (Figure 4b).

[0294] Conclusions

[0295] With the aim of developing a new class of anti-influenza agents, the inventors studied a series of compounds, and evaluated their activities against IAV both in vitro and in vivo, using appropriate cellular and animal models. Compounds containing at least two carboxylic acid groups showed improved antiviral activity and reduced cytotoxicity across both series.

[0296] Overall, the findings support the potential of the compounds of the current invention as promising candidates for anti-influenza therapy.

[0297] Example 2 : Further experiments

[0298] To complement these data, further experiments were carried out with the CS17 and AHM269 compounds following the procedure detailed in Example 1. The results are presented on Figure 5. Administration of CS17 and AHM269 at 2 days post-infection increased mouse survival to 80% and 40% respectively (Figure 5a). Furthermore, treatment with AHM269 at 4 and 5 days post-infection increased survival to 80% (Figure 5b). References:

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[0303] 5. Jefferson T, Jones MA, Doshi P, et al (2014) Neuraminidase inhibitors for preventing and treating influenza in adults and children. Cochrane Database of Systematic Reviews 2018:. https: / / doi.Org / 10.1002 / 14651858.CD008965.pub4

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[0305] 7. Tavares LP, Teixeira MM, Garcia CC (2017) The inflammatory response triggered by Influenza virus: a two edged sword. Inflamm Res 66:283-302. https: / / doi.org / 10.1007 / s0001 1 - 016-0996-0

[0306] 8. O’Neill LAJ, Kishton RJ, Rathmell J (2016) A guide to immunometabolism for immunologists. Nat Rev Immunol 16:553-565. https: / / doi.org / 10.1038 / nri.2016.70

[0307] 9. Pearce EJ, Pearce EL (2018) Immunometabolism in 2017: Driving immunity: all roads lead to metabolism. Nat Rev Immunol 18:81-82. https: / / doi.org / 10.1038 / nri.2017.139

[0308] 10. Rambold AS, Pearce EL (2018) Mitochondrial Dynamics at the Interface of Immune Cell Metabolism and Function. Trends Immunol 39:6-18. https: / / doi.org / 10.1016 / j-it.2017.08.006

[0309] 11. Cezard A, Monard S, Brea-Diakite D, et al (2021 ) [Metabokines reviewed: Essential mediators of anti-infectious immunity]. Med Sci (Paris) 37:342-348. https: / / doi.org / 10.1051 / medsci / 2021031

[0310] 12. Rao M, Dodoo E, Zumla A, Maeurer M (2019) Immunometabolism and Pulmonary Infections: Implications for Protective Immune Responses and Host-Directed Therapies. Front Microbiol 10:962. https: / / doi.org / 10.3389 / fmicb.2019.00962

[0311] 13. Guillon A, Brea-Diakite D, Cezard A, et al (2022) Host succinate inhibits influenza virus infection through succinylation and nuclear retention of the viral nucleoprotein. The EMBO Journal 41 :e108306. https: / / doi.org / 10.15252 / embj.2021 108306

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Claims

1. CLAIMS1. Compound of formula (I):whereinR1 is selected from C1-6 alkyl, benzene, pyridine, pyrimidine, pyrazine, pyridazine, thiophene,R2, Rs are independently selected from H, NH2, NH(CI-6 alkyl), N( C1-6 alkyl)2, CO2Rs, OH, SH, S-S-R7, halogen, SO3R8, O( Ci-6alkyl), P(O)(OH)2,R3, R4, Re are independently selected from H, Na, K, C1-6 alkyl,R7is a C1-6 alkyl optionally substituted by n COOH moiety, n being an integer from 1 to 12,Rs is selected from Na and K, for use in a method of treatment of a viral lung infection and / or of an adverse immune response to a viral lung infection, said method comprising administering to a subject in need thereof an effective amount of compound of formula (I) or of a pharmaceutically acceptable salt thereof.

2. Compound for use in a method according to claim 1 , wherein said compound is of formula (la), (lb), (Ic), (Id) or (le):whereinR2, Rs are independently selected from H, NH2, NH(CI-6 alkyl), N( C1-6 alkyl)2, CO2Re, OH, SH, S-S-R7, halogen, SO3R8, O( Ci-6alkyl), P(O)(OH)2,R3, R4, Rs are independently selected from H, Na, K, C1-6 alkyl,R7is a C1-6 alkyl optionally substituted by n COOH moiety, n being an integer from 1 to 12,R8is selected from Na and K.

3. Compound for use in a method according to claim 1 or 2, wherein the compound is selected from the group consisting of:

4. Compound for use in a method according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of:

5. Compound for use in a method according to any one of claims 1 to 4, wherein the viral lung infection is caused by a respiratory virus preferably selected from an influenza virus, a coronavirus, a respiratory syncytial virus, a parainfluenza virus, a metapneumovirus, a rhinovirus, an adenovirus, a varicella-zoster virus, a cytomegalovirus, a paramyxovirus such as Nipah virus, an enterovirus and a bocavirus.

6. Compound for use in a method according to any one of claims 1 to 5, wherein the viral lung infection is caused by an influenza virus.

7. Compound for use in a method according to any one of claims 1 to 6, wherein the method is applied to treat the viral lung infection.

8. Compound for use in a method according to any one of claims 1 to 7, wherein the method is applied to treat an adverse immune response to the viral lung infection.

9. Compound for use in a method according to any one of claim 1 to 7, wherein the method is applied to prevent a lung viral infection from escalating to an adverse immune response.

10. Compound for use in a method according to any one of claims 1 to 9, wherein the adverse immune response to viral lung infection is selected from a hyper-inflammatory immune response, a dyspnea, a tachypnea, a pneumonia in particular an acute pneumonia, an exacerbation of a chronic respiratory disease such as asthma or chronic obstructive pulmonary disease, a sepsis, a septic shock, a cytokine storm or an acute respiratory distress syndrome (ARDS).

11. Compound for use in a method according to any one of claims 1 to 10, wherein the compound is administered between 2 and 14 days post infection.

12. Compound for use in a method according any one of claims 1 to 1 1 , wherein the compound is used alone or in combination with one or more active substance selected from the group consisting of antivirals, antibiotics, and / or antalgics.

13. Compound for use in a method according to any one of claims 1 to 12, wherein said treatment is for preventing the occurrence of a lung viral infection, the method comprising administering the compound in a subject that is not infected with a respiratory virus.

14. Compound for use in a method according to any one of claims 1 to 13, wherein the composition is administered intrapulmonary, nasally, orally, enterally, intravenously, intramuscularly and subcutaneously.

15. Pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3 and a pharmaceutically acceptable support for use in a method as defined in any one of the preceding claims.

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