How to use 5'-adenosine diphosphate ribose (ADPR)

Abstract

Provided are pharmaceutical compositions for treating, managing, or preventing diseases or conditions associated with RNA viruses, diseases or conditions associated with herpes viruses, diseases or conditions associated with Sirtuin 6 (Sirt6), diseases or conditions associated with Pax6, and diseases or conditions associated with p53. The present invention provides a pharmaceutical composition comprising 5'-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopic species, or polymorph thereof.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is a continuation of U.S. Provisional Patent Application No. 62 / 648,585, filed March 27, 2018, and U.S. Provisional Patent Application No. 62 / 648,585, filed July 2, 2018. This application claims the benefit of U.S. Provisional Patent Application No. 62 / 693,021, filed on the same date, each of which is hereby incorporated by reference in its entirety. The entirety of which is incorporated herein by reference.

[0002] 1. FIELD OF THE INVENTION The present invention relates to diseases or conditions associated with RNA viruses, diseases or conditions associated with herpes viruses, pathologies, Sirtuin 6 (Sirt6)-associated diseases or pathologies, Pax6-associated diseases or pathologies, and 5'-adenosine for treating, managing, or preventing diseases or conditions associated with p53 and p53-associated disorders or conditions - Patents.com The present invention is directed to methods of using diphosphate ribose (ADPR), and compositions thereof. [Background technology]

[0003] 2. BACKGROUND OF THE INVENTION An RNA virus is a virus that has RNA (ribonucleic acid) as its genetic material. are usually single-stranded RNA (ssRNA), but can also be double-stranded RNA (dsRNA). Notable human diseases caused by bronchitis and bronchiolitis (human respiratory syndrome) Hemorrhagic fever (Ebola virus, etc.), severe acute respiratory syndrome (coronavirus, etc.) common cold (rhinovirus, parainfluenza virus, coronavirus, etc.), Influenza, Hepatitis C, West Nile, polio, measles, and acquired immunodeficiency syndrome (AIDS) including human immunodeficiency virus (HIV).

[0004] Human respiratory syncytial virus (HRSV) is a pathogen that infects immunocompetent as well as immunocompromised individuals. HRSV is a single-stranded, negative-sense RNA virus. HRSV typically causes respiratory tract infections that affect all parts of the respiratory tract. SV is a major cause of lower respiratory tract disease, bronchiolitis and pneumonia in infants and children. In the United States, 60% of infants are infected during their first RSV season, and nearly all children are infected during the second People are infected with this virus by the age of 3. 2-3% of people infected with HRSV have a bronchiole infection. Natural infection with HRSV induces protective immunity, which is Possibly more so than other respiratory viral infections, which may diminish over time and therefore Infants can be infected multiple times. Sometimes, infants are infected twice within a single HRSV season. Severe HRSV infections are increasingly being observed among elderly patients. Young adults can be reinfected every 5 to 7 years, and symptoms typically resemble a sinus infection or the common cold. The incubation period (from infection to the onset of symptoms) is 4-5 days. In adults, HRSV causes mainly mild symptoms, which are distinct from the common cold and mild illnesses. The Centers for Disease Control and Prevention (CDC) reports that HRSV is the most prevalent cause of death in children under 1 year of age in the United States. is the most common cause of bronchiolitis (inflammation of the small airways of the lungs) and pneumonia in children (Hall et al., 2009, N. Engl. J. Med., 360(6):588-598; Iwane et al., 2013, J. Infect. Dis., 208(Suppl. 3): 2-3; Rose et al., 2018, Respiratory Syncy tial Virus Seasonality - United States, 2014-2017, MMWR Morb. Mortal Wkly. Rep., 67:71-76). For some children, HRSV can cause bronchiolitis, which requires hospitalization. This can lead to severe respiratory illness, which can be fatal in rare cases. Other common HRSV symptoms among infants are fatigue, indigestion, and difficulty eating. Loss of appetite or decreased appetite and fever are possible. According to Falsey's study (Falsey et al., 2005, N. Engl. J. Med., 352(17):1749-1759), four winters in Rochester, New York. During the respiratory season (1999-2003), HRSV infections were reported annually. The incidence was an average of 5.5% (3-7%) of healthy adults aged 65 years or older (i.e., without COPD or CHF). % range), and high-risk adults aged 21 years and older (i.e., those diagnosed with chronic heart or lung disease) In this same population, HRSV was responsible for 9.6% of these hospitalizations. Based on discharge diagnoses, HRSV accounted for 10.6% of hospitalizations for pneumonia and 10.6% for chronic obstructive pulmonary disease (COPD). 11.4% for cerebrovascular disease, 7.2% for asthma, and 5.4% for congestive heart failure (CHF) In adults aged 65 years and older, HRSV infection is , which is estimated to cause 14,000 deaths annually in US adults.

[0005] Herpesviridae is a large family of DNA viruses that cause disease in animals and humans. Members of this family are also known as herpes viruses. The Greek origin of the name herpes comes from the latent, relapsing nature typical of this group of viruses. Refers to an infectious disease. Herpes viruses can cause latent or lytic infections. There are five types of herpes viruses - herpes simplex virus types 1 and 2 (known as HSV-1 and HSV-2) ), varicella-zoster virus (causes chickenpox and shingles), Epstein-Barr virus (mononuclear associated with several diseases, including cytopenia and some cancers), and cytomegalovirus They are highly prevalent in humans; more than 90% of adults are infected with at least one of these species. The virus is transmitted to humans through a latent form, which persists in most humans. There are nine herpes viruses known to infect: HSV-1 and HSV-2 (same Varicella-zoster virus (VZV, also known as HHV1 and HHV2), and varicella-zoster virus (VZV, which by its ICTV name HHV-3), Epstein-Barr virus (EBV or HHV-4), human cytomegalovirus virus (HCMV or HHV-5), human herpesvirus 6A and 6B (HHV-6A and HHV-6B), human herpesvirus Herpesvirus 7 (HHV-7), and Kaposi's sarcoma-associated herpesvirus (KSHV, also known as HHV-8) knowledge).

[0006] Decreased activity of the protein Sirtuin 6 (Sirt6) is associated with viral and age-related diseases. Diabetes, type 2 diabetes, respiratory disorders, chronic lung disease, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary Fibrosis, cystic fibrosis, eye disease, diabetic retinopathy, retinal disease, retinal detachment, adult macular degeneration , glaucoma, liver disease, non-alcoholic steatohepatitis, chronic hepatitis infection, neurodegenerative disorders (e.g. Alzheimer's disease), disorders that cause cognitive decline, trauma that causes brain or spinal cord damage, cancer, chemotherapy-induced neuropathy, neuropathy associated with ischemic or traumatic events, Autoimmune diseases, disorders related to excessive inflammation, pulpitis, mitochondrial diseases or disorders, heart Vascular disease, stroke, stress-related disorders, arthritis, osteoarthritis, preterm labor, decreased Disorders that benefit from cellular glycolytic activity, muscle tissue damage associated with hypoxia or ischemia, coagulation disorders, fungal infections, ischemia, chronic pain associated with brain and / or spinal cord disease, high blood pressure, or It is associated with multiple diseases, such as any combination thereof.

[0007] PAX6 (paired box protein Pax-6), aniridia type II protein (AN2) or oculome Bin (also known as oculorhombin) is a transcription factor that is highly conserved throughout evolution. It is a key regulator of eye development in both vertebrates and invertebrates. In addition, the PAX6 protein is expressed in the eye (Kroeber et al., 2010, Human Molecular Genetics, 19(17) :3332-3342; Shaham et al., 2012, Progress in Retinal and Eye Research, 31(5):35 1-376; Swisa et al., Journal of Clinical Investigation, 127(1):230-243; Osumi et al. (2008, Stem Cells, 26(7):1663-1672), the brain and spinal cord (central nervous system), and the pancreas It is believed that it activates the genes involved in the formation of the brain. Continued PAX6 expression throughout the lifespan maintains the proper phenotype of these cells and is essential for the maintenance of normal function after cell injury. It is important in helping to avoid metaplastic reactions in the thyroid. Sexual mutations include iris agenesis or hypoplasia, corneal opacity, foveal and optic nerve dysplasia, and white iris. It is the cause of aniridia, a condition associated with various abnormalities of ocular development, including glaucoma. Currently, mutations in PAX6 are associated with Peters anomaly, central corneal opacity (vitiligo), corneal endothelial (and A condition characterized by focal defects of the cornea (where the lenses are attached) and iridocorneal adhesions. In mice with heterozygous mutations in Pax6, the eye defects are generally more extreme. In most cases, the eyes are less than half their normal size (microphthalmia). The anterior chamber of the eye is lost, the retina is abnormally folded, and the lens is missing or small. Approximately 50-75% of patients with aniridia develop an anterior subcapsular cataract in preadolescence or early adulthood. This can lead to increased intraocular pressure (IOP), which commonly leads to optic nerve damage and glaucoma. This occurs via the aqueous humor circulation system. Aqueous humor is secreted by the ciliary processes into the posterior chamber of the eye, and also drains from the eye through the trabecular meshwork and Schlemm's canal, which are localized in the iridocorneal angle of the anterior chamber. Studies of heterozygous Pax6-deficient mice, an animal model of aniridia, have shown defects in trabecular meshwork differentiation and The authors confirmed the complete absence of the canal of Schlemm and the iris. Similar structural defects are observed in humans with aniridia. This well-described IOP elevation and glaucoma phenotype are associated with glaucoma.

[0008] The cells of the human body are constantly exposed to various stresses and threats to the integrity of the human genome. (Li et al., 2015, Journal of Cellular Physiology, 230(10):2318-2327). The inhibitory protein p53 (also known as TP53) induces apoptotic cell death or cell cycle arrest By doing so, they play a key role in successfully defending against these threats. p53 has also been shown to be important in regulating normal immune responses and inflammatory diseases It is involved in metabolism, stem cell maintenance, conception, and response to viral or other microbial infections. also plays an important role in the immune system (Munoz-Fontela et al., 2016, Nature Reviews Immun In the absence of stress, p53 levels and activity are significantly increased by apoptosis. must be kept low to prevent lethal activation of the mitotic and senescence pathways. (Haupt et al., 1997, Nature, 387(6630):296-299). However, DNA damage and other stresses During the assay, p53 regulates a range of innate immune, cell cycle, apoptosis, and other regulatory genes. It is released from its repressed state to induce transcription and transcription of genes. The enzyme MDM2 (mouse double minute 2 protein) is a cytotoxic agent that protects against various p53-activating agents, including DNA damage. MDM2 activity is determined by phosphorylation of p53. MDM2 activity is also regulated by post-translational modifications such as ATP-dependent cleavage, which interfere with its interaction with p53. (Shangary and Wang, 2009, Annual Review of Pharmacology and Toxicology, 49:223-241), or inhibition of its heterodimer formation with MDM4 (also known as MDMX) (Roxburgh et al., 2012, Carcinogenesis, 33(4):791-798) and directly inhibited Deficiency of p53 can lead to cancer susceptibility, impaired innate immunity, and susceptibility to viral infections. , impaired recovery from bacterial infections, impaired wound healing, increased cataract formation, vascular disease, and Associated with abnormal tissue aging (Madenspacher et al., 2013, The Journal of Experimental Biology). Mental Medicine, 210(5):891-904; Wiley et al., 2011, Disease Models & Mechanism s, 4(4):484-495; Tabas, 2001, Circulation Research, 88(8):747-749; Hirota et al., 2010, Journal of Clinical Investigation, 120(3):803-815).

[0009] 5'-Adenosine diphosphate ribose (ADPR) is a small molecule of natural origin, which is commercially available Previous studies have shown that ADPR inhibits Sirt6 at concentrations of 10-1000 μM. (Madsen et al., 2016, J. Biol. Chem., 291(13):7128-7141). Summary of the Invention

[0010] (3. Summary of the Invention) A method for treating, managing, or preventing an RNA virus-associated disease or condition in a patient. The method further comprises administering an effective amount of 5'-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt thereof. any salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs thereof The method comprises administering the compound, or a pharmaceutical composition thereof, to a patient, wherein the patient is suffering from an RNA virus-associated The methods of treating a patient having or at risk of developing a disease or condition are provided herein. will be done.

[0011] A method for treating, managing, or preventing a herpes virus-associated disease or condition in a patient. The method comprises administering to the patient an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof, Hydrates, tautomers, stereoisomers, isotopic species, or polymorphs, or pharmaceutical compositions thereof wherein the patient has a herpes virus-associated disease or condition. Provided herein are methods for treating or being at risk of developing the disease.

[0012] Treating, managing, or preventing a disease or condition associated with Sirtuin 6 (Sirt6) deficiency in a patient The method comprises administering to a patient an effective amount of ADPR, or a pharmaceutically acceptable salt thereof. , solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs. wherein the patient has a disease or condition associated with a Sirt6 deficiency; or In one embodiment, a patient is at risk of developing the disease. Diseases or conditions that can be treated, managed, or prevented by increasing Sirt6 activity in A method for treating, managing, or preventing a condition, the method comprising administering to a patient an effective amount of ADPR, or Pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic molecules thereof wherein the patient is administered a species or polymorph thereof; have or develop a disease or condition that is treatable, manageable, or preventable by In one embodiment, a method is provided herein for administering to a patient at risk of developing a steroid hormone receptor agonist (SHR)-mediated ischemic heart failure. ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof; and administering isotopic or polymorphic forms of Sirt6 to a patient in need thereof. In another aspect, a method for increasing the amount and / or activity of an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof; administering a stereoisomer, isotopic species, or polymorph to a patient in need thereof. Provided herein are methods for increasing the activity of Sirt6 in

[0013] A method for treating, managing, or preventing a disease or condition associated with a Pax6 deficiency in a patient. The method comprises administering to the patient an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. including administering a solute, tautomer, stereoisomer, isotopic species, or polymorph; The patient herein is at risk of having or developing a disease or condition associated with Pax6 deficiency. In one embodiment, a method is provided herein for detecting Pax6 activity in a patient. Treating, managing, or preventing a disease or condition that is treatable, manageable, or preventable by increasing or a method for preventing the onset of rheumatoid arthritis, the method comprising administering to a patient an effective amount of ADPR, or a pharmaceutically acceptable salt thereof. any salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs thereof that may be present wherein the patient has a condition treatable or manageable by increasing Pax6 activity. having or being at risk of developing a disease or condition that is preventable or preventable In one embodiment, a patient is administered an effective amount of ADPR, or a pharmaceutically acceptable salt thereof. Acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs and / or administering to a subject in need thereof a compound comprising: In another embodiment, a method for administering to a patient an effective amount of ADPR, or Pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and isotopic species of and methods for increasing the activity of Pax6 in a patient in need thereof, including administering a compound or polymorph thereof. A method for doing so is provided herein.

[0014] A method for treating, managing, or preventing a disease or condition associated with p53 deficiency in a patient. The method comprises administering to the patient an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. including administering a solute, tautomer, stereoisomer, isotopic species, or polymorph; Here, the patient is at risk of having or developing a disease or condition associated with p53 deficiency. In one embodiment, a method for assessing p53 activity in a patient is provided herein. Treating, managing, or preventing a disease or condition that is treatable, manageable, or preventable by increasing or a method for preventing the onset of rheumatoid arthritis, the method comprising administering to a patient an effective amount of ADPR, or a pharmaceutically acceptable salt thereof. any salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs thereof that may be present wherein the patient has a disease treatable or manageable by increasing p53 activity. having or being at risk of developing a disease or condition that is preventable or preventable In one embodiment, a patient is administered an effective amount of ADPR, or a pharmaceutically acceptable salt thereof. Acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs Increasing the amount and / or activity of p53 in a patient in need thereof, including administering In another embodiment, a method for administering to a patient an effective amount of ADPR, or Pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and isotopic species of and methods for increasing p53 activity in a patient in need thereof, including administering a compound or polymorph thereof. A method for doing so is provided herein.

[0015] In one embodiment, the RNA virus-associated disease or condition is an HRSV-associated disease or condition. .

[0016] In certain embodiments, an RNA virus-associated disease or condition (e.g., an HRSV-associated disease or condition) is A condition is a disease or condition that affects any part of the eye, ear, mouth, upper respiratory tract, or lower respiratory tract. In one embodiment, an RNA virus-associated disease or condition (e.g., HRSV-associated disease) is Diseases or conditions include diseases of the eye, conjunctivitis, keratitis, keratoconjunctivitis, ulcerative infectious keratitis, superficial Keratitis, interstitial keratitis, uveitis, acute glaucoma, blepharitis, otitis media, otitis externa, gingivitis, mucous membranes Meningitis, pharyngitis, tonsillitis, rhinitis, sinusitis, laryngitis, pseudomembranous laryngitis, tracheitis, bronchitis, septicemia Bronchitis, bronchopneumonia, pneumonia, asthma exacerbation, chronic obstructive pulmonary disease exacerbation, emphysema exacerbation, or The present invention is selected from, but not limited to, exacerbation of chronic lung disease.

[0017] In one embodiment, the herpes virus-associated disease or condition is an HSV-1-associated disease or condition. is.

[0018] In certain embodiments, a herpes virus-associated disease or condition (e.g., HSV-1-associated) Diseases or conditions) affecting the eyes, ears, mouth, upper respiratory tract, lower respiratory tract, urogenital tract, skin, brain, liver, spleen In one embodiment, the disease or condition is a disease or condition affecting any part of the liver, kidney, or nervous system. Herpes virus-associated diseases or conditions (e.g., HSV-1-associated diseases or conditions) include diseases on the eye. , conjunctivitis, keratitis, keratoconjunctivitis, ulcerative infectious keratitis, superficial keratitis, interstitial keratitis, grapes Ureitis, acute glaucoma, blepharitis, otitis media, otitis externa, gingivitis, mucositis, pharyngitis, tonsillitis, rhinitis, Sinusitis, laryngitis, pseudomembranous laryngitis, tracheitis, bronchitis, bronchiolitis, bronchopneumonia, pneumonia, vaginitis, dermatitis, asthma exacerbation, chronic obstructive pulmonary disease exacerbation, emphysema exacerbation, or increased risk of chronic lung disease Selected from evil, but not limited to:

[0019] In certain embodiments, a disease or condition associated with a Sirt6 deficiency or an increase in Sirt6 activity is identified. Diseases or conditions that can be treated, managed, or prevented by adding Disease, age-related diseases, diabetes, type 2 diabetes, respiratory disorders, chronic pulmonary disease, chronic obstructive pulmonary disease Pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, eye disease, diabetic retinopathy, retinal disease, Retinal detachment, adult macular degeneration, glaucoma, liver disease, non-alcoholic steatohepatitis, chronic hepatitis infection Neurodegenerative disorders (e.g., Alzheimer's disease), disorders resulting in cognitive decline, brain or spinal cord injury traumatic injury, cancer, chemotherapy-induced neuropathy, ischemic or traumatic events Neuropathies, autoimmune diseases, disorders related to excessive inflammation, pulpitis, mitochondrial dysfunction Disease or disorder, cardiovascular disease, stroke, stress-related disorders, arthritis, osteoarthritis , preterm labor, disorders that benefit from reduced cellular glycolytic activity, associated with hypoxia or ischemia chronic conditions associated with muscle tissue damage, blood clotting disorders, fungal infections, ischemia, brain and / or spinal cord disease The symptoms may be sexual pain, high blood pressure, or any combination thereof.

[0020] In certain embodiments, the present invention relates to a method for treating a disease or condition associated with a Pax6 deficiency or an increase in Pax6 activity. Diseases or conditions that can be treated, managed, or prevented by using Associated eye diseases, aniridia-related keratopathy, keratoconus, uveitis, diabetic retinopathy, retinal Membrane disease, retinal detachment, acute retinal necrosis, Gillespie syndrome, Peters anomaly, WAGR syndrome, Lyme disease, presbyopia, myopia, glaucoma, congenital glaucoma, cataracts, corneal damage or infection, keratitis , keratoconjunctivitis, adult macular degeneration, diabetic retinopathy, postoperative recovery from eye or brain surgery, limbal stem cells deficiency, diabetes, type 2 diabetes, neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease) (e.g., cognitive impairment), cerebellar ataxia, hyposmia, nystagmus, auditory processing disorder, memory impairment Memory impairment, autism, mental retardation, trauma resulting in brain or spinal cord injury, stroke, or any combination thereof It is a combination.

[0021] In certain embodiments, a disease or condition associated with a p53 deficiency or an increase in p53 activity is treated. Diseases or conditions that can be treated, managed, or prevented by using antiviral drugs include viral diseases, infectious diseases, and Age-related diseases, diabetes, type 2 diabetes, respiratory disorders, chronic lung disease, chronic obstructive pulmonary disease, Asthma, idiopathic pulmonary fibrosis, cystic fibrosis, eye diseases, diabetic retinopathy, retinal diseases, retinal detachment , adult macular degeneration, glaucoma, liver disease, non-alcoholic steatohepatitis, chronic hepatitis infection, neurology Degenerative disorders (e.g., Alzheimer's disease and Parkinson's disease), disorders that result in cognitive decline, brain or trauma, cancer, chemotherapy-induced neuropathy, ischemic or traumatic spinal cord injury Event-related neuropathy, autoimmune diseases, disorders related to excessive inflammation, pulpitis, myocardial infarction, pituitary disease or disorder, cardiovascular disease, stroke, stress-related disorders, arthritis, Osteoarthritis, preterm labor, disorders that benefit from reduced cellular glycolytic activity, hypoxia or For ischemia-related muscle tissue damage, blood clotting disorders, fungal infections, ischemia, and brain and / or spinal cord diseases In certain embodiments, the associated chronic pain, hypertension, or any combination thereof. and diseases or conditions associated with p53 deficiency or treatable by increasing p53 activity. Treatable or preventable diseases or conditions include wound healing disorders, cataracts, presbyopia, or viral infections. It is a cancer that occurs secondary to infection.

[0022] In certain embodiments, ADPR or a pharmaceutically acceptable salt, solvate, or hydrate thereof tautomers, stereoisomers, isotopic species, or polymorphs may be administered topically, orally, parenterally, orally. In one embodiment, the AD described herein is administered by mucosal or inhalation routes of administration. The ADPR is administered by the inhalation route of administration. In one embodiment, the ADPR described herein is administered topically. In one embodiment, local administration is by administration to the interior of a cell or tissue surface. In a specific embodiment, local administration to an internal cell or tissue surface is By aerosolization, spraying, oral delivery, injection or similar methods onto any surface of the respiratory tract. In another specific embodiment, local administration to an internal cell or tissue surface is via administration to an internal cell or tissue surface, such as ... By oral delivery, injection, or enema to any surface of the body (from the abdomen to the anus). local administration to internal cells or tissue surfaces, parenteral injection or infusion into any internal organ; In another embodiment, topical administration is by topical application to, but not limited to, the skin, eyes, nails, To external cell or tissue surfaces, including hair or ears.

[0023] In certain embodiments, the methods provided herein involve administering to a subject an ADPR, or a pharmaceutically acceptable salt thereof. Acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs and administering to a patient a pharmaceutical composition containing the formulation and an excipient, diluent, or carrier. include.

[0024] In specific embodiments, for use in the compositions and methods provided herein The ADPR compound is in the form of its dilithium salt.

[0025] In certain embodiments, ADPR, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, The compound, tautomer, stereoisomer, isotopic species, or polymorph may be present in combination with other drugs. In certain embodiments, the other pharmaceutical agent is an antiviral compound.

[0026] In one aspect, the methods provided herein include: (i) administering to a patient a therapeutically effective amount of ADPR, or a solvate or hydrate thereof; tautomers, stereoisomers, isotopic species, or polymorphs, and (ii) one or more pharmaceutical and administering a pharmaceutical composition containing a commercially acceptable excipient, diluent, or carrier. wherein the amount of ADPR in the pharmaceutical composition is in the range of about 0.001% w / w to about 10% w / w of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises dilithium ADPR. [Brief explanation of the drawings]

[0027] (4. Brief description of the drawings) [Figure 1] Figure 1 is a graph of luminescence versus dilithium ADPR (Li2-ADPR) concentration. The amount of luminescence directly quantifies the amount of HRSV replication in A549 cells. These results demonstrate significant dose-dependent inhibition of HRSV replication with increasing concentrations of Li2-ADPR. The inhibition pattern was similar on days 1 and 2 after the initial infection on day 0.

[0028] [Figure 2] Figure 2 is a graph of the percentage of infected A549 cells versus Li2-ADPR concentration. Cell infection was determined by the presence of green fluorescence in each cell. The data show that increasing Li2-ADPR concentrations resulted in a significant decrease in the percentage of infected cells on days 1 and 2 after the initial inoculation on day 0.

[0029] [Figure 3] Figure 3 is a graph of the percentage of infected primary human airway epithelial cells versus Li2-ADPR concentration. Cell infection was determined by the presence of luciferase activity. The data show that increasing Li2-ADPR concentrations resulted in a significant decrease in the percentage of infected cells on days 1 and 3 after the primary inoculation on day 0.

[0030] [Figure 4] FIG. 4 depicts plate images from the plaque inhibition assay described in Example 4.

[0031] [Figure 5] Figure 5 shows the gel (a) and quantitative assessment of Sirt6 deacetylation activity (b) in the presence of Li2-ADPR. In this example, deacetylation activity is expressed as the reciprocal of H3K9Ac acetylation (as indicated by anti-H3K9Ac antibody) divided by the total H3 histone concentration, which was then converted to %.

[0032] [Figure 6] FIG. 6 shows the average results of Sirt6 activation studies with Li2-ADPR concentrations between 0.01 nM and 1000 nM (0.00001 μM and 1 μM).

[0033] [Figure 7] FIG. 7 shows the time-dependent increase in protein concentration for Sirt6 in human corneal epithelial cells incubated with 60 μM Li2-ADPR.

[0034] [Figure 8] Figure 8 shows the time-dependent increase in protein concentration for Pax6 (isoforms 5a and 6) and cytokeratin 12 in human corneal epithelial cells incubated with 60 μM Li2-ADPR. All band intensities were calculated relative to "no treatment."

[0035] [Figure 9] FIG. 9 shows the time-dependent increase in protein concentration for p53 in human corneal epithelial cells incubated with 60 μM Li2-ADPR.

[0036] [Figure 10] FIG. 10 shows images of in silico docking of ADPR with MDM2 (a) at the protein interface between MDM2 and MDM4 as a heterodimer, and (b) at the protein binding interface between MDM2 and p53.

[0037] [Figure 11] Figure 11 shows lung tissue RSV titers (a), lung tissue interferon gamma (IFNγ) (b), and lung tissue transforming growth factor beta (TGFβ) (c). Each figure compares results from control (phosphate-buffered saline) and 0.5% Li2-ADPR-treated cotton rats. Tissue samples were obtained on day 5 of treatment (50 μL administered by nasal inhalation twice daily) after infection with RSV.

[0038] [Figure 12] FIG. 12 shows the effect of Li2-ADPR on plaque inhibition against HSV-1 in A549 cells. DETAILED DESCRIPTION OF THE INVENTION

[0039] (5. Detailed Description) (5.1 Definition) As used herein, the term "ADPR" refers to ADPR and its pharmaceutically acceptable salts. Also includes salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs. It is understood to include.

[0040] As used herein, the term "dose" refers to a dose or doses administered at one time. , ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof A dose may contain one unit dosage form. Alternatively, more than one unit dosage form (e.g., a single dose containing two tablets) may be used. or in less than one unit dosage form (e.g., a single dose may contain 1 / 2 of a tablet ) can even be included.

[0041] As used herein, the term "daily dose" refers to the amount of ADP administered in a 24-hour period. R, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or equivalent thereof. The daily dose refers to the amount of a compound administered all at once. The daily dose may be administered once a day (i.e., once daily dosing), or alternatively, the daily dose may be administered in a single dose ... commercially acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, if The polymorphs are administered twice daily, three times daily, four times daily, five times daily, or The dosage may be divided into six doses per day, or even consecutively throughout the day.

[0042] As used herein, the terms "patient" or "subject" include, but are not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice mammals, including monkeys, chickens, turkeys, quail, or guinea pigs, etc. In one embodiment, the term "patient" or "subject" as used herein In one embodiment, the term "patient" as used herein refers to a mammal. "Subject" or "subject" means a human.

[0043] As used herein, an "effective amount" is an amount that provides a therapeutic benefit in the treatment of a disease. ADPR, or and its pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic forms thereof. In certain embodiments, the disease is an RNA virus-associated disease. In certain embodiments, the disease is an HRSV-associated disease or condition. In certain embodiments, the disease is a disease or condition associated with a herpes virus ( For example, diseases or conditions associated with herpes simplex virus type 1 (HSV-1). In embodiments, the disease is a disease or condition associated with a Sirt6 deficiency or a disease or condition associated with increased Sirt6 activity. In certain embodiments, the disease or condition is treatable, manageable, or preventable by administering a therapeutic agent to the patient. In such cases, the disease may be a disease or condition associated with a Pax6 deficiency or an increased Pax6 activity. In certain embodiments, the disease or condition is treatable, manageable, or preventable. The disease may be a disease or condition associated with p53 deficiency or may be treatable by increasing p53 activity. It is a treatable, manageable, or preventable disease or condition.

[0044] As used herein, the terms "prevent" and "preventing" are used interchangeably. The terms "venting" and "prevention" are art-recognized and refer to the treatment of an RNA virus-associated disease. or condition, HRSV-associated disease or condition, herpesvirus-associated disease or condition, HSV-1-associated disease a disease or condition, a disease or condition associated with Sirt6 deficiency, or a disease or condition caused by increasing Sirt6 activity and diseases or conditions treatable, manageable, or preventable by Pax6 deficiency. or a disease treatable, manageable, or preventable by increasing Pax6 activity, or Conditions, diseases or conditions associated with p53 deficiency, or treatable by increasing p53 activity When used in connection with a condition, such as a disease or condition that is manageable, manageable, or preventable, the present invention provides It is well understood in the field and has been shown to improve the overall health of patients receiving the composition compared to patients not receiving the composition. In this context, the administration of a compound that reduces the frequency of symptoms of the condition or delays its onset.

[0045] As used herein, the terms "treat" and "treating" are used interchangeably. "treatment" and "treatment" refer to the treatment of symptoms, clinical signs, and / or symptoms in a manner that improves or stabilizes the patient's condition. The term "cure" refers to the reversal, reduction, or prevention of symptoms and the underlying pathology of a condition. "Treat" and "treatment" also refer to the eradication or amelioration of a disease or symptoms associated with that disease. In certain embodiments, such terms refer to patients suffering from such diseases. Minimizing the spread or worsening of the disease as a result of the administration of the compounds disclosed herein. In certain embodiments, the disease is an RNA virus-associated disease or condition. In certain embodiments, the disease is an HRSV-associated disease or condition. In certain embodiments, the disease is a herpesvirus-associated disease or condition. In certain embodiments, the disease is an HSV-1-associated disease or condition. Diseases or conditions associated with Sirt6 deficiency or treatable by increasing Sirt6 activity, In certain embodiments, the disease is a disease or condition that is manageable or preventable. Diseases or conditions associated with x6 deficiency or treatable or manageable by increasing Pax6 activity In certain embodiments, the disease is a p53 deficiency or preventable disease or condition. Diseases or conditions associated with p53 loss or that can be treated or managed by increasing p53 activity or a preventable disease or condition.

[0046] As used herein, the terms "manage" and "managing" are used interchangeably. g) and "management" are the measures to prevent the recurrence of a particular disease or condition in an affected patient. to prevent, reduce patient mortality, and / or reduce the risk of death associated with the disease or condition being managed; The objective of this study is to provide a method for treating rheumatoid arthritis, including maintaining the reduction in severity or avoidance of symptoms achieved.

[0047] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical composition for treating an RNA virus-associated disease or illness. conditions (e.g., HRSV-associated diseases or conditions), herpesvirus-associated diseases or conditions (e.g., HSV- 1-related diseases or conditions), diseases or conditions associated with Sirt6 deficiency, and diseases or conditions associated with Sirt6 deficiency, and diseases or conditions treatable, manageable, or preventable by Pax6 deficiency. , diseases or conditions treatable, manageable, or preventable by increasing Pax6 activity, p5 3 Diseases or conditions associated with deficiency or treatable or manageable by increasing p53 activity used or prescribed in the treatment, management, or prevention of a disease or condition that is preventable or preventable This refers to a composition suitable for the intended treatment.

[0048] As used herein, the term "pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable based on sound medical judgment. within the limits of safety, can come into contact with human tissue without excessive toxicity, irritation, allergic reaction, etc. These salts are suitable for use in combination with other drugs and are commensurate with a reasonable benefit / risk ratio. cormorant.

[0049] As used herein, and unless otherwise indicated, the terms "about" or "approximately" "These" refers to the allowable error for a particular value determined by a person skilled in the art. The error depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to a range of 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to a given value or 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.05% of the range or within 0.005%.

[0050] All references to singular terms or limitations of the invention are to the singular unless otherwise indicated or mentioned. Unless the contrary is clearly implied by the context in which it is used, A letter or limitation is inclusive, and vice versa.

[0051] As used herein, all combinations of method or process steps are included unless otherwise indicated. Unless otherwise specified or the context in which the combination is made makes it clear that the opposite is true Unless otherwise implied, they may be performed in any order.

[0052] The compositions and methods of the present invention may be prepared without the addition of any additional or optional raw materials, ingredients, or components described herein. Compositions and methods of the general type described or otherwise set forth herein The invention may include essential elements and limitations of the invention described herein, along with limitations useful in the art. , may consist solely of, or consist essentially of, such elements and limitations. It can consist of only the definition.

[0053] (5.2 5'-Adenosine diphosphate ribose (ADPR)) The uses and compositions provided herein include 5'-adenosine diphosphate ribose (AD PR; ADP-ribose; Adenosine 5'-(trihydrogen diphosphate), P'→5-ester with D-ribose Adenosine 5'-(trihydrogen pyrophosphate), 5'→5-ester with D-ribofuranose; Adenosine 5'-diphosphate, D-ribose ester; Adenosine 5'-pyrophosphate, D-ribose ester 5'→5-ester with ribofuranose; Ribofuranose, 5-(adenosine 5'-pyrphosphoryl) -D-ribose; Adenosine 5'-diphosphoribose; Adenosine diphosphate ribose; Adeno Adenosine diphosphoribose; Adenosine pyrophosphate-ribose; Adenosine diphosphate ribose Regarding (s).

[0054] ADPR is a small molecule of natural origin that is well known in the chemical literature. It is often represented by the general formula C 15 H 23 N5O 14 P2 and corresponds, for example, to the general structure of the following formula (I): It encompasses a variety of salts such as: [ka]

[0055] ADPR can be readily prepared by methods well known in the chemical arts. It is commercially available as a raw material, for example, purchased from Sigma or Sigma-Aldrich. You can enter.

[0056] The ADPR compounds are characterized in that the basic nitrogen-containing groups are methyl, ethyl, propyl chlorides, bromides, and iodides. and lower alkyl halides such as butyl; dimethyl, diethyl, dibutyl and Dialkyl sulfates such as diamyl; decyl chloride, bromide and iodide, lauryl, myristyl and stearyl; aryl such as benzyl bromide and phenethyl; quaternized with materials such as alkyl halides, as well as many others, The term "amino acid" may also include derivatives thereof.

[0057] Examples of acids that can be used to form pharmaceutically acceptable acid addition salts of ADPR include hydrochloric acid, Inorganic acids such as hydrobromic, sulfuric and phosphoric acids, as well as oxalic, maleic, succinic and and organic acids such as citric acid.

[0058] During the final isolation and purification of ADPR, the acid moiety is replaced with a pharmaceutically acceptable metal ion. a suitable base such as, but not limited to, a hydroxide, carbonate, or bicarbonate; can be made basic by reacting with ammonia or with organic primary, secondary or tertiary amines. Salts may be prepared in situ. Non-limiting examples of pharmaceutically acceptable salts include lithium (dilithium) salts. sodium (including disodium), potassium, calcium, magnesium Alkali metals, alkaline earth metals such as aluminum, zinc, cobalt, and copper salts, etc. , transition metals or post-transition metals, as well as ammonium, tetramethylammonium, tetramethylammonium Triethylammonium, methylamine, dimethylamine, trimethylamine, triethyl Non-toxic quaternary ammonia and amine caps, including amine, diethylamine, ethylamine, etc. Other representative compounds useful for the formation of base addition salts include salts based on the following captions: The functional amines include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.

[0059] In one embodiment, for use in the compositions and methods provided herein ADPR compounds include, but are not limited to, lithium hydroxide or sodium hydroxide. Hydrolysis of nicotinamide adenine dinucleotide (NAD+) in the presence of alkaline bases In such an embodiment, the ADPR thus synthesized is These compounds are isolated in the form of mono- or di-salts of the metal ions of the corresponding bases.

[0060] In specific embodiments, the compositions and methods for use in the methods provided herein include In one embodiment, the ADPR compound is in the form of its sodium salt. is in the form of its monosodium salt. In another embodiment, the ADPR compound is in the form of its di-sodium salt. It is in the form of a thorium salt.

[0061] In another specific embodiment, the compositions and uses in the methods provided herein The ADPR compound for is in the form of its lithium salt. In another embodiment, the ADPR compound is in the form of its dilithium salt. In one embodiment, the ADPR compound is in the form of one or more sodium, lithium salts. combinations of potassium, calcium, magnesium, zinc, cobalt, and / or copper salts It is a form.

[0062] 5.3 Treatment, management and prevention methods Provided herein are methods for treating an RNA virus-associated disease or condition (e.g., HRSV-associated diseases or conditions), herpes virus-associated diseases or conditions (e.g., HSV-1-associated diseases or conditions), Diseases or conditions associated with Sirt6 deficiency can be treated or managed by increasing Sirt6 activity or preventable disease or condition, disease or condition associated with Pax6 deficiency, increasing Pax6 activity Diseases or conditions treatable, manageable, or preventable by the administration of p53 or associated with p53 deficiency a disease or condition that is treatable, manageable, or preventable by increasing p53 activity a method for treating, managing, or preventing a disease or condition that can be treated by an RNA virus-associated disease a disease or condition (e.g., an HRSV-associated disease or condition), a herpesvirus-associated disease or condition (e.g., (e.g., HSV-1-associated disease or condition), disease or condition associated with Sirt6 deficiency, or increasing Sirt6 activity and diseases or conditions treatable, manageable, or preventable by administering the same to a subject, diseases associated with Pax6 deficiency. or a condition, disease or condition that can be treated, managed, or prevented by increasing Pax6 activity. conditions, diseases or conditions associated with p53 deficiency, or treatable by increasing p53 activity, Patients who have or are at risk of developing a treatable or preventable disease or condition ADPR or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, a method comprising administering a compound, isotopic species, or polymorph, or a pharmaceutical composition thereof, to a subject; do.

[0063] In certain embodiments, provided herein are methods for treating an RNA virus-associated disease. or condition (e.g., HRSV-associated disease or condition), herpesvirus-associated disease or condition (e.g., , HSV-1-associated diseases or conditions), diseases or conditions associated with Sirt6 deficiency, and increasing Sirt6 activity and diseases or conditions that are treatable, manageable, or preventable by the use of Pax6 deficiency. is a pathology, disease or condition that can be treated, managed, or prevented by increasing Pax6 activity. conditions, diseases or conditions associated with p53 deficiency, or treatable or manageable by increasing p53 activity A method for treating or preventing a disease or condition that is treatable or preventable by an RNA virus. herpesvirus-associated disease or condition (e.g., HRSV-associated disease or condition), herpesvirus-associated disease or condition pathological conditions (e.g., HSV-1-associated diseases or conditions), diseases or conditions associated with Sirt6 deficiency, Sirt6 activity Diseases or conditions that can be treated, managed, or prevented by increasing Pax6 activity, including those related to Pax6 deficiency Related diseases or conditions that can be treated, managed, or prevented by increasing Pax6 activity or a disease or condition associated with p53 deficiency, or a disease or condition associated with increasing p53 activity. have or develop a disease or condition that is treatable, manageable, or preventable An at-risk patient is administered an effective amount of ADPR or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , tautomers, stereoisomers, isotopic species, or polymorphs, or pharmaceutical compositions thereof. The method includes:

[0064] In certain embodiments, provided herein are methods for treating an RNA virus-associated disease or condition. Methods for treating, managing, or preventing a condition (e.g., an HRSV-associated disease or condition) in a patient The method comprises administering an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. , tautomers, stereoisomers, isotopic species, or polymorphs to a patient. wherein the patient has an RNA virus-associated disease or condition (e.g., an HRSV-associated disease or condition). have or are at risk of developing it.

[0065] In certain embodiments, provided herein are methods for treating an RNA virus-associated disease or condition. and methods for treating, managing, or preventing a condition (e.g., an HRSV-associated disease or condition) in a patient. Thus, the method comprises administering an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, or administering a pharmaceutical composition containing a tautomer, stereoisomer, isotopic species, or polymorph to a patient; wherein the patient is suffering from an RNA virus-associated disease or condition (e.g., HRSV-associated disease), have or are at risk of developing a disease or condition.

[0066] In certain embodiments, the RNA virus-associated disease or condition is asthma or chronic obstructive pulmonary disease. This includes, but is not limited to, diseases.

[0067] In certain embodiments, the RNA virus-associated disease or condition is caused by an RNA virus. RNA viruses are classified into Coronaviridae viruses, Pneumobilidae viruses, and rus, Paramyxoviridae virus, Picornaviridae virus, or Orthomyxoviridae virus In certain embodiments, the Coronaviridae virus is Coronavirus or SARS, Pneumobilidae virus, human respiratory syncytial virus The virus is a human parainfluenza virus (HRSV), and the Paramyxoviridae family virus is a human parainfluenza virus (HPV). , measles virus, or mumps virus, and the Picornaviridae virus is a rhinovirus. and Orthomyxoviridae viruses are influenza viruses. In certain embodiments, the RNA virus is a Pneumobilidae virus. In one embodiment, the RNA virus is HRSV.

[0068] In certain embodiments, provided herein are methods for treating an RNA virus-associated disease or condition. to patients with a condition (e.g., an HRSV-associated disease or condition), or to patients with an RNA virus-associated disease or condition administering an effective amount of ADP to a patient at risk of developing a condition (e.g., an HRSV-associated disease or condition); R, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or equivalent thereof. and administering to a patient a disease or condition associated with an RNA virus, including administering a methylisothiazol-3-one or ... 1. A method for treating, managing, or preventing a disease or condition, such as an HRSV-associated disease or condition, comprising administering to a subject a RNA virus-associated A virus-associated disease or condition (e.g., an HRSV-associated disease or condition) can affect the eyes, ears, mouth, or upper respiratory tract. In some embodiments, the RNA is a disease or condition affecting the esophagus, esophagus, or lower respiratory tract. A virus-associated disease or condition (e.g., an HRSV-associated disease or condition) can include diseases on the eye, conjunctiva, inflammation, keratitis, keratoconjunctivitis, corneal abrasion, ulcerative infectious keratitis, superficial keratitis, interstitial keratitis, Uveitis, acute glaucoma, blepharitis, otitis media, otitis externa, gingivitis, mucositis, pharyngitis, tonsillitis, rhinitis inflammation, sinusitis, laryngitis, pseudomembranous laryngitis, tracheitis, bronchitis, bronchiolitis, bronchopneumonia, lung Select from inflammation, asthma exacerbation, chronic obstructive pulmonary disease exacerbation, emphysema exacerbation, or chronic lung disease exacerbation In certain embodiments, the viral vectors include, but are not limited to, RNA viruses. Associated diseases or conditions (e.g., HRSV-associated diseases or conditions) include conjunctivitis, keratitis, and keratoconjunctivitis. , pharyngitis, tonsillitis, laryngitis, rhinitis, sinusitis, bronchitis, bronchiolitis, or pneumonia. In one embodiment, an RNA virus-associated disease or condition (e.g., an HRSV-associated disease or condition) is The condition is bronchitis, bronchiolitis, or pneumonia. In another embodiment, the viral infection is an RNA virus-related infection. Related diseases or conditions (e.g., HRSV-associated diseases or conditions) include pharyngitis, tonsillitis, sinusitis, or laryngitis. In another embodiment, an RNA virus-associated disease or condition (e.g., HRSV) In some embodiments, the inflammatory bowel disease or condition is keratitis, conjunctivitis, or keratoconjunctivitis. In this case, the RNA virus-associated disease or condition is an HRSV-associated disease or condition.

[0069] In certain embodiments, provided herein are methods for treating herpesvirus-associated diseases or treat, manage, or prevent a condition (e.g., an HSV-1-associated disease or condition) in a patient The method comprises administering an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof, Administering hydrates, tautomers, stereoisomers, isotopic species, or polymorphs to patients wherein the patient has a herpes virus-associated disease or condition (e.g., HSV-1-associated disease or condition), have or are at risk of developing a medical condition.

[0070] In certain embodiments, provided herein are methods for treating herpesvirus-associated diseases or treat, manage, or prevent a condition (e.g., an HSV-1-associated disease or condition) in a patient The method comprises administering an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof, Pharmaceutical compositions containing hydrates, tautomers, stereoisomers, isotopic species, or polymorphs to a patient, wherein the patient is suffering from a herpes virus-associated disease or condition (e.g., have or are at risk of developing an HSV-1-associated disease or condition.

[0071] In certain embodiments, the herpes virus-associated disease or condition is asthma or chronic obstructive pulmonary disease. These include, but are not limited to, chronic lung disease.

[0072] In certain embodiments, the herpes virus-associated disease or condition is an ophthalmic, cutaneous, urinary, reproductive tract, vagina, nerves, nervous system, brain, liver, spleen, pharynx, tonsils, or any other organ described herein It is a disease or condition that affects the tissues.

[0073] In certain embodiments, provided herein are methods for treating diseases or conditions associated with Sirt6 deficiency. A method of treating, managing, or preventing a condition in a patient, the method comprising administering an effective amount of ADPR or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isomer, or derivative thereof and administering to a patient a specific isoform or polymorph thereof, wherein the patient has a condition associated with Sirt6 deficiency. have or are at risk of developing an associated disease or condition.

[0074] In certain embodiments, provided herein are methods for treating diseases or conditions associated with Sirt6 deficiency. A method of treating, managing, or preventing a condition in a patient, the method comprising administering an effective amount of ADPR or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isomer, or derivative thereof The method includes administering to a patient a pharmaceutical composition containing a solute molecular species or polymorph, wherein the patient A person has or is at risk of developing a disease or condition associated with Sirt6 deficiency. do.

[0075] In certain embodiments, provided herein are methods for increasing Sirt6 activity. Treating, managing, or preventing a more treatable, manageable, or preventable disease or condition in a patient The method comprises administering an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof. administering a compound, hydrate, tautomer, stereoisomer, isotopic species, or polymorph to a patient wherein the patient has a condition treatable, manageable, or In one embodiment, the subject has or is at risk of developing a preventable disease or condition. In the present invention, the methods provided herein include increasing Sirt6 deacetylation activity. In another embodiment, the methods provided herein comprise Sirt6 deacetylation of histone 3 activity. In another embodiment, the methods provided herein include increasing histogenesis. In another embodiment, the method comprises increasing Sirt6 deacetylation of lysine residues in phospholipase 3 (SIR6). The methods provided herein increase Sirt6 deacetylation of lysine 9 (K9) of histone 3 activity. This includes adding

[0076] In certain embodiments, provided herein are methods for increasing Sirt6 activity. Treating, managing, or preventing a more treatable, manageable, or preventable disease or condition in a patient The method comprises administering an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof. Pharmaceutical compositions containing hydroxybenzoates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs and administering to a patient a composition comprising the compound of formula (I) or (II) to treat the patient by increasing Sirt6 activity. the risk of having or developing a disease or condition that is manageable, controllable, or preventable There is.

[0077] In certain embodiments, a disease or condition associated with a Sirt6 deficiency or an increase in Sirt6 activity is Diseases or conditions that can be treated, managed, or prevented by adding These include, but are not limited to, obstructive pulmonary disease.

[0078] In certain embodiments, a disease or condition associated with a Sirt6 deficiency or an increase in Sirt6 activity is Diseases or conditions that can be treated, managed, or prevented by adding , age-related diseases, diabetes, type 2 diabetes, respiratory disorders, chronic lung diseases, chronic obstructive pulmonary disease Disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, eye disease, diabetic retinopathy, retinal disease, retinal Desquamation, adult macular degeneration, glaucoma, liver disease, non-alcoholic steatohepatitis, chronic hepatitis infection, Neurodegenerative disorders (e.g., Alzheimer's disease), disorders resulting in cognitive decline, brain or spinal cord injury related to trauma, cancer, chemotherapy-induced neuropathy, ischemic or traumatic events Neuropathy, autoimmune diseases, disorders related to excessive inflammation, pulpitis, mitochondrial diseases Diseases or disorders, cardiovascular disease, stroke, stress-related disorders, arthritis, osteoarthritis, premature ejaculation Preterm labor, disorders that benefit from reduced cellular glycolytic activity, muscle damage associated with hypoxia or ischemia Chronic pain associated with muscle tissue damage, blood clotting disorders, fungal infections, ischemia, brain and / or spinal cord disease pain, high blood pressure, or any combination thereof.

[0079] In certain embodiments, provided herein is an effective amount of ADPR, or a pharmaceutical formulation thereof. commercially acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, if and administering to the patient a polymorph or a polymorphic form of Sirt6. In certain embodiments, the methods provided herein are methods for increasing the activity of is an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, administration of stereoisomers, isotopic species, or polymorphs to a patient in need thereof. The present invention relates to a method for increasing Sirt6 activity in patients with glaucoma.

[0080] In certain embodiments, provided herein are methods for treating diseases or conditions associated with Pax6 deficiency. A method for treating, managing, or preventing a condition in a patient, the method comprising administering an effective amount of ADPR, or and its pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic forms thereof. and administering to a patient a gene or polymorphism associated with Pax6 deficiency. Having or being at risk of developing a disease or condition.

[0081] In certain embodiments, provided herein are methods for treating diseases or conditions associated with Pax6 deficiency. A method for treating, managing, or preventing a condition in a patient, the method comprising administering an effective amount of ADPR, or and its pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic forms thereof. and administering to a patient a pharmaceutical composition containing the polymorph or polymorph, wherein the patient , have or are at risk of developing a disease or condition associated with Pax6 deficiency.

[0082] In certain embodiments, provided herein are methods for increasing Pax6 activity. Treating, managing, or preventing a disease or condition in a patient that is treatable, manageable, or preventable by The method comprises administering an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof, administering a compound, hydrate, tautomer, stereoisomer, isotopic species, or polymorph to a patient wherein the patient has a condition treatable, manageable, or preventable by increasing Pax6 activity. Having or being at risk of developing a preventable disease or condition.

[0083] In certain embodiments, provided herein are methods for increasing Pax6 activity. Treating, managing, or preventing a disease or condition in a patient that is treatable, manageable, or preventable by The method comprises administering an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof, Pharmaceutical compositions containing hydroxybenzoates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs The method comprises administering a composition to a patient, wherein the patient has a condition treatable by increasing Pax6 activity. have or are at risk of developing a disease or condition that is treatable, manageable, or preventable be.

[0084] In certain embodiments, the present invention relates to a disease or condition associated with a Pax6 deficiency or an increase in Pax6 activity. Diseases or conditions that can be treated, managed, or prevented by adding These include, but are not limited to, diseases of the liver.

[0085] In certain embodiments, the present invention relates to a disease or condition associated with a Pax6 deficiency or an increase in Pax6 activity. Diseases or conditions that can be treated, managed, or prevented by adding eye diseases related to aniridia, keratopathy related to aniridia, keratoconus, uveitis, diabetic retinopathy, Retinal disease, retinal detachment, acute retinal necrosis, Gillespie syndrome, Peters anomaly, WAGR syndrome, Dry eyes, presbyopia, myopia, glaucoma, congenital glaucoma, cataracts, corneal damage or infection, corneal inflammation, keratoconjunctivitis, adult macular degeneration, diabetic retinopathy, postoperative recovery from eye or brain surgery, limbal stem cell Alveolar deficiency, diabetes, type 2 diabetes, neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease) Diseases, etc.), disorders that cause cognitive decline, cerebellar ataxia, hyposmia, nystagmus, auditory processing disorders, Memory impairment, autism, mental retardation, trauma resulting in brain or spinal cord injury, stroke, or any of these It is a combination.

[0086] In certain embodiments, provided herein is an effective amount of ADPR, or a pharmaceutical formulation thereof. commercially acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, if and / or administering to the patient a polymorph or polymorphs thereof. In certain embodiments, provided herein are methods for increasing the activity of a , an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, or derivative thereof. administration of isomers, isotopic species, or polymorphs to a patient. The present invention relates to a method for increasing the activity of Pax6 in patients with glaucoma.

[0087] In certain embodiments, provided herein are methods for treating diseases or conditions associated with p53 deficiency. A method for treating, managing, or preventing a condition in a patient, the method comprising administering an effective amount of ADPR, or and its pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic forms thereof. and administering to a patient a gene or polymorphism associated with p53 deficiency. Having or being at risk of developing a disease or condition.

[0088] In certain embodiments, provided herein are methods for treating diseases or conditions associated with p53 deficiency. A method for treating, managing, or preventing a condition in a patient, the method comprising administering an effective amount of ADPR, or and its pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic forms thereof. and administering to a patient a pharmaceutical composition containing the polymorph or polymorph, wherein the patient , have or are at risk of developing a disease or condition associated with p53 deficiency.

[0089] In certain embodiments, provided herein are methods for increasing p53 activity. Treating, managing, or preventing a disease or condition in a patient that is treatable, manageable, or preventable by The method comprises administering an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof, administering a compound, hydrate, tautomer, stereoisomer, isotopic species, or polymorph to a patient wherein the patient has a disease treatable, manageable, or preventable by increasing p53 activity. have or are at risk of developing a preventable disease or condition. In accordance with the present invention, the methods provided herein increase p53 protein levels by inhibiting MDM2. This includes adding

[0090] In certain embodiments, provided herein are methods for increasing p53 activity. Treating, managing, or preventing a disease or condition in a patient that is treatable, manageable, or preventable by The method comprises administering an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof, Pharmaceutical compositions containing hydroxybenzoates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs The method includes administering a composition to a patient, wherein the patient has a disease treatable by increasing p53 activity. have or are at risk of developing a disease or condition that is treatable, manageable, or preventable be.

[0091] In certain embodiments, a disease or condition associated with p53 deficiency or increasing p53 activity Diseases or conditions that can be treated, managed, or prevented by using the method include viral diseases, aging, and diseases caused by diabetes, type 2 diabetes, respiratory disorders, chronic lung disease, chronic obstructive pulmonary disease, asthma Breath, idiopathic pulmonary fibrosis, cystic fibrosis, eye disease, diabetic retinopathy, retinal disease, retinal detachment, Adult macular degeneration, glaucoma, cataracts, presbyopia, liver disease, non-alcoholic steatohepatitis, chronic hepatitis Infectious diseases, neurodegenerative disorders (e.g., Alzheimer's disease and Parkinson's disease), and cognitive decline traumatic brain or spinal cord injury; cancer; cancer secondary to viral infection; chemotherapy-induced Neuropathies induced by steroids, neuropathies associated with ischemic or traumatic events, autoimmune diseases , disorders associated with excessive inflammation, dental pulpitis, mitochondrial diseases or disorders, cardiovascular diseases, Stroke, stress-related disorders, arthritis, osteoarthritis, preterm labor, decreased cellular glycolysis disorders that would benefit from activity, muscle tissue damage associated with hypoxia or ischemia, blood clotting disorders, Fungal infection, ischemia, chronic pain associated with brain and / or spinal cord disease, hypertension, impaired wound healing, or is any combination thereof.

[0092] In certain embodiments, provided herein is an effective amount of ADPR, or a pharmaceutical formulation thereof. commercially acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, if and / or administering to the patient a polymorph thereof. In certain embodiments, provided herein are methods for increasing the activity of a , an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, or derivative thereof. administration of isomers, isotopic species, or polymorphs to a patient. The present invention relates to a method for increasing p53 activity in patients with leukemia.

[0093] In certain embodiments, provided herein are methods for treating an RNA virus-associated disease or condition. conditions (e.g., HRSV-associated diseases or conditions), herpesvirus-associated diseases or conditions (e.g., HSV-1-associated diseases or conditions, diseases or conditions associated with Sirt6 deficiency, increasing Sirt6 activity and diseases or conditions treatable, manageable, or preventable by administering the same to a subject, diseases associated with Pax6 deficiency. or a condition, disease or condition that can be treated, managed, or prevented by increasing Pax6 activity. conditions, diseases or conditions associated with p53 deficiency, or treatable by increasing p53 activity, Patients who have or are at risk of developing a treatable or preventable disease or condition an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, , including administering stereoisomers, isotopic species, or polymorphs of RNA viruses. Disease or condition (e.g., HRSV-associated disease or condition), herpesvirus-associated disease or condition conditions (e.g., HSV-1-associated diseases or conditions), diseases or conditions associated with Sirt6 deficiency, diseases or conditions associated with Sirt6 activity a disease or condition that can be treated, managed, or prevented by increasing the activity of Pax6 deficiency Associated diseases or conditions treatable, manageable, or preventable by increasing Pax6 activity a disease or condition that can be treated by increasing p53 activity, a disease or condition that is associated with a p53 deficiency, or A method for treating, managing, or preventing a treatable, manageable, or preventable disease or condition. Thus, the ADPR compound is administered by topical, oral, parenteral, transmucosal or inhalation routes of administration. In one embodiment, the ADPR described herein is administered by the inhalation route of administration. In one embodiment, the ADPR described herein is administered by a topical route of administration. In certain embodiments, local administration is to an internal cell or tissue surface. In this regard, topical administration to internal cell or tissue surfaces is possible by aerosolization, spraying, or injection onto any surface of the respiratory tract. In another specific embodiment, the internal cells are Topical administration to any surface of the cyst or tissue is also possible, as is oral administration to any surface of the digestive tract (e.g., from the mouth to the anus). In another specific embodiment, to an internal cell or tissue surface. In another embodiment, the local administration of is by parenteral injection or infusion into any internal organ. Topical administration can be to external tissue, including, but not limited to, the skin, eyes, nails, hair, or ears. or to the tissue surface.

[0094] In one embodiment, an RNA virus-associated disease or condition (e.g., an HRSV-associated disease or condition) is Pathological conditions) include the eyes, ears, nose, mouth, nasal pharynx, oropharynx, pharynx, larynx, trachea, bronchi, and tracheoli at least one of the respiratory tract, including but not limited to the bronchi, lungs, and alveoli Respiratory disorders or viral infections of one tissue.

[0095] In one embodiment, a herpes virus-associated disease or condition (e.g., an HSV-1-associated disease or condition) is The area of ​​the eye, ear, nose, mouth, nasal pharynx, oropharynx, pharynx, larynx, trachea, bronchi, and cerebrospinal fluid (e.g., bronchial tubes) At least part of the respiratory tract, including but not limited to the bronchi, lungs, and alveoli Another example is a respiratory disorder or viral infection of one tissue.

[0096] In one embodiment, a disease or condition associated with a Sirt6 deficiency or increasing Sirt6 activity is Diseases or conditions that can be treated, managed, or prevented by The airways, including the pharynx, oropharynx, pharynx, larynx, trachea, bronchi, bronchioles, lungs, and alveoli. including, but not limited to, respiratory disorders or viruses in at least one tissue of the respiratory tract. It is a bacterial infection.

[0097] In one embodiment, provided herein is a method for treating a patient exposed to an RNA virus. In one embodiment, the present invention provides a method for treating, managing, or preventing an infectious disease by administering the method of claim 1 to a subject comprising administering to said subject a therapeutic agent provided herein. The method for treating, managing, or preventing infection in patients exposed to HRSV infection is described. In a specific embodiment, ADPR is in the form of its dilithium salt.

[0098] In one embodiment, an RNA virus-associated disease or condition (e.g., an HRSV-associated disease or condition) is In certain embodiments, the ocular condition is an ocular disease. Microbial infections of the tissue, conjunctivitis, keratitis, keratoconjunctivitis, corneal abrasion, ulcerative infectious keratitis, superficial keratitis The inflammation is ocular inflammation, interstitial keratitis, uveitis, acute glaucoma, or blepharitis. In this case, the eye disease is infectious keratoconjunctivitis.

[0099] In one embodiment, a herpes virus-associated disease or condition (e.g., an HSV-1-associated disease or condition) is In certain embodiments, the ocular disease is a condition characterized by a vascular disease of at least one part of the eye. Microbial infection of the tissues, conjunctivitis, keratitis, keratoconjunctivitis, corneal abrasion, ulcerative infectious keratitis, surface The condition is lamellar keratitis, interstitial keratitis, uveitis, acute glaucoma, or blepharitis. In the eye disease is infectious keratoconjunctivitis.

[0100] In one embodiment, a disease or condition associated with a Sirt6 deficiency or increasing Sirt6 activity. Diseases or conditions treatable, manageable, or preventable by certain methods are eye diseases. In some embodiments, the eye disease is a microbial infection of at least one tissue of the eye, conjunctivitis, keratitis, or the like. , keratoconjunctivitis, corneal abrasion, ulcerative infectious keratitis, superficial keratitis, interstitial keratitis, uveitis, In a specific embodiment, the eye disease is infectious keratoconjunctivitis. be.

[0101] In one embodiment, an RNA virus-associated disease or condition (e.g., an HRSV-associated disease or condition) is In a specific embodiment, the disease is caused by an RNA virus-associated disease or The condition (e.g., HRSV-associated disease or condition) is caused by inflammation of the cornea and / or conjunctiva. In a specific embodiment, the RNA virus-associated disease or condition is caused by pulmonary inflammation. In a specific embodiment, ADPR is in the form of its dilithium salt.

[0102] In one embodiment, a herpes virus-associated disease or condition (e.g., an HSV-1-associated disease or condition) is In a specific embodiment, the condition is caused by inflammation. Associated diseases or conditions (e.g., HSV-1 associated diseases or conditions) include corneal and / or conjunctival inflammation. In a specific embodiment, ADPR is in the form of its dilithium salt. do.

[0103] In one embodiment, a disease or condition associated with a Sirt6 deficiency or increasing Sirt6 activity. The disease or condition treatable, manageable, or preventable by In a specific embodiment, a disease or condition associated with a Sirt6 deficiency or an increase in Sirt6 activity is The diseases or conditions that can be treated, managed, or prevented by In a specific embodiment, ADPR is in the form of its dilithium salt. is.

[0104] In one embodiment, a disease or condition associated with a Pax6 deficiency or an increase in Pax6 activity is Many of the more treatable, manageable, or preventable diseases or conditions are caused by inflammation. In a specific embodiment, a disease or condition associated with a Sirt6 deficiency or increasing Sirt6 activity is Diseases or conditions that can be treated, managed, or prevented by In a specific embodiment, ADPR is in the form of its dilithium salt. be.

[0105] In one embodiment, a disease or condition associated with a p53 deficiency or by increasing p53 activity Diseases or conditions that are treatable, manageable, or preventable are caused by inflammation. In a specific embodiment, the present invention relates to a method for treating a disease or condition associated with a p53 deficiency or by increasing p53 activity. Diseases or conditions that are treatable, manageable, or preventable by corneal and / or conjunctival inflammation are In a specific embodiment, ADPR is in the form of its dilithium salt.

[0106] In one embodiment, the administering step comprises administering ADPR and a metal salt, wherein AD The total amount of PR and metal salt per dose is in the range of about 0.001 mg to about 5 mg. In another embodiment, each dose is 10 μl to 200 μl. It is 80 μl.

[0107] In one embodiment, the administering step comprises administering the pharmaceutical composition in solution form. In one embodiment, the solution is administered to the eye 1 to 8 times per day. The solution is administered into the eye 1 to 24 times per day.

[0108] In one embodiment, the method further comprises administering at least one dose at least one month prior to the administering step. The method includes storing the composition for at least 3 months, at least 6 months, or at least 1 year.

[0109] 5.4 Combination Therapy In certain embodiments, ADPR or a pharmaceutically acceptable salt, solvate, or hydrate thereof tautomers, stereoisomers, isotopic species, or polymorphs, or pharmaceutical compositions thereof, may be used interchangeably with other Such combination therapy may be administered in combination with other drugs, such as steroids, steroids, or other similar drugs, without the need for simultaneous administration of the individual therapeutic components. This may be achieved by means of sequential or separate administration. When administered as a component of a method, the ADPR and other medications disclosed herein act synergistically. so that the daily dose of either or both of the components may be The dose of either component may be reduced compared to the dose normally given. When administered as a component of a therapeutic regimen, the ADPRs and other medications disclosed herein The effects may be additive, so that the daily dose of each of the components is higher than that normally given as monotherapy. The dosage of either component is similar or the same as that of the other component.

[0110] In certain embodiments, the other medicament is an antiviral compound or metal salt. In some embodiments, the other medicament is an antiviral compound. The medicines are abacavir, acyclovir, adefovir, amantadine, and ampoules. Lenavir, Ampligen, Arbidol, Atazanavir, Balavir, Sidof Dolutegravir, Darunavir, Delavirdine, Didanovir Shin, docosanol, edoxudine, efavirenz, elvitegravir, emtricita Bin, Enfuvirtide, Entecavir, Ecolibel, Famciclovir, Fomivirsen, fosamprenavir, foscarnet, fosphonet, ganciclovir , Ibacitabine, Immunovir, Idoxuridine, Imiquimod, Indinavir, Inosine , type III interferon, type II interferon, type I interferon, interferon Lon, Lamivudine, Lopinavir, Lovirid, Maraviroc, Moro Xyzidine, methisazone, nelfinavir, nevirapine, nexavir, nitazoxanide, Norvir, oseltamivir, peginterferon alpha-2a, penciclovir, pera Mivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine acetaminophen, ritonavir, pyramidine, saquinavir, sofosbuvir, stavudine, tetanus Laprevir, Tenofovir, Tenofovir Disoproxil, Tipranavir, Trimethoprim Fluridine, Trizivir, Tromantadine, Truvada, Valaciclovir, Valganciclo Vicriviroc, vidarabine, viramidine, zalcitabine, zanamibi In some embodiments, the other medication is ribavirin, cidovudine, or zidovudine. In a specific embodiment, the other pharmaceutical agent is cyclovir, acyclovir, or ganciclovir. is ribavirin.

[0111] In certain embodiments, the other pharmaceutical agent is a lithium, zinc, cobalt, or copper salt. In certain embodiments, the other medicament is lithium benzoate, lithium bromide, lithium chloride. Lithium, lithium sulfate, lithium tetraborate, lithium acetate, zinc chloride, zinc sulfate, zinc bromide , cobalt chloride, cobalt bromide, copper bromide (CuBr2), copper chloride (CuCl2) or copper sulfate. In a specific embodiment, the other pharmaceutical agent is lithium chloride.

[0112] 5.5 Dosage and Administration Regimens In certain embodiments, an RNA virus-associated disease or condition (e.g., an HRSV-associated disease or condition) is or condition), herpes virus-associated disease or condition (e.g., HSV-1-associated disease or condition), Si Diseases or conditions associated with rt6 deficiency that can be treated or managed by increasing Sirt6 activity. or preventable diseases or conditions, diseases or conditions associated with Pax6 deficiency, and diseases or conditions that increase Pax6 activity. diseases or conditions that are treatable, manageable, or preventable by the use of p53 inhibitors, diseases or conditions associated with p53 deficiency, is a pathology or disease that can be treated, managed, or prevented by increasing p53 activity The pathological conditions are approximately 0.0001 mg / kg to approximately 1000 mg / kg, approximately 0.001 mg / kg to approximately 100 mg / kg, and approximately 0.1 mg / kg to approximately 10 mg / kg, or about 0.1 mg / kg to about 5.0 mg / kg of ADPR, or a pharmaceutically acceptable salt or solvate thereof. Any compound, hydrate, tautomer, stereoisomer, isotopic species, or polymorphic form described herein may be used. Administered to patients who have or are at risk of developing a disease or condition listed It can be treated by

[0113] In certain embodiments, the pharmaceutical composition comprises ADPR, or a pharmaceutically acceptable salt thereof. Salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs are generally The content may be 0.00001 to 100%, for example 0.001 to 10%, or 0.01% to 2% by weight.

[0114] In certain embodiments, an RNA virus-associated disease or condition (e.g., an HRSV-associated disease) is also or condition), herpes virus-associated disease or condition (e.g., HSV-1-associated disease or condition) , diseases or conditions associated with Sirt6 deficiency, treatable and manageable by increasing Sirt6 activity a disease or condition that can be prevented, a disease or condition associated with Pax6 deficiency, a disease or condition that can be prevented by increasing Pax6 activity, diseases or conditions that can be treated, managed, or prevented by administering a disease or condition, or a disease that can be treated, managed, or prevented by increasing p53 activity The disease or condition may be about 0.005 mg to about 1000 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, or about 0.01 mg about 0.01 mg to about 0.1 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5.0 mg, 0.1 mg to about 1 mg of ADP R, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or equivalent thereof. The isomers, molecular species, or polymorphs may be used to identify those with or without the diseases or conditions described herein. or may be administered to a patient at risk of developing the disease. In the present invention, ADPR or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, or derivative thereof is The concentration of isomers, isotopic species, or polymorphs is in the range of about 0.05 mg / mL to about 30 mg / mL. In another embodiment, ADPR, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, The concentration of the compound, tautomer, stereoisomer, isotopic species, or polymorph is about 1 mg / mL to about 20 mg / mL range.

[0115] In certain such embodiments, the ADPR described herein is administered topically, intravenously, or intravenously. It is administered by oral, parenteral, transmucosal, or inhalation routes of administration. The ADPR described herein is administered by the inhalation route of administration. The ADPR described herein is administered by topical administration. In one embodiment, topical administration is administered by internal administration. In a specific embodiment, the method is performed on an internal cell or tissue surface. Topical administration can be by aerosolization, nebulization, spraying, oral delivery, intratracheal instillation, intrabronchial, or inhalation. In another specific embodiment, by injection into the surface of an internal cell or tissue. The desired administration may be by oral delivery to any surface of the digestive tract (e.g., from the mouth to the anus), injection, or enema. In another specific embodiment, local administration to an internal cell or tissue surface is administered to any internal organ. In another embodiment, local administration is by parenteral injection or infusion into an external cell or organ. In one embodiment, the external cell or tissue surface is the skin, eye, nail, or This includes, but is not limited to, the surface of the ears, hair, or ears. In the present invention, the ADPR described herein is administered topically at a concentration ranging from about 0.05 mg / mL to about 30 mg / mL. In another embodiment, the ADPR described herein is administered in a range of about 1 mg / mL to about 20 mg / mL. In some embodiments, administration is intravenous, intraarterial, or This is done by intraductal injection.

[0116] In certain embodiments, an RNA virus-associated disease or condition (e.g., an HRSV-associated disease) is also or condition), herpes virus-associated disease or condition (e.g., HSV-1-associated disease or condition) , diseases or conditions associated with Sirt6 deficiency, or treatable by increasing Sirt6 activity, Treatable or preventable diseases or conditions include those with doses of about 0.005 mg to about 1000 mg, about 0.01 mg to about 100 mg, and about 0.01mg to about 10mg, about 0.01mg to about 1mg, about 0.01mg to about 0.1mg, about 0.1mg to about 10mg, about 0.1mg to about 5.0 mg, 0.1 mg to about 1 mg of ADPR, or a pharmaceutically acceptable salt or solvate thereof, Hydrates, tautomers, stereoisomers, isotopic species, or polymorphs may be used in combination with other compounds described herein. It should be administered to patients who have or are at risk of developing a disease or condition that is In one embodiment, ADPR, or a pharmaceutically acceptable salt thereof, , solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphic forms are In another embodiment, ADPR, or a pharmaceutical composition thereof, is in the range of about 0.05 mg / mL to about 30 mg / mL. commercially acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, if The concentration of the polymorph is in the range of about 1 mg / mL to about 20 mg / mL. In such manner, the ADPRs described herein may be administered topically, orally, parenterally, transmucosally, or by inhalation. In one embodiment, ADPR is administered by the inhalation route. In one embodiment, the ADPR described herein is administered by topical administration. In one embodiment, local administration is to an internal cell or tissue surface. In certain embodiments, local administration to an internal cell or tissue surface is achieved by administration to any surface of the respiratory tract. By aerosolization, spray, oral delivery, injection or similar methods. In this context, local administration to internal cells or tissue surfaces is achieved by administering the drug to any part of the digestive tract (e.g., from the mouth to the anus). In another specific embodiment, the cells within the Local administration to a tissue surface can be by parenteral injection or infusion into any internal organ. In such cases, topical administration includes, but is not limited to, application to the skin, eyes, nails, hair, or ears. In a specific embodiment, the AD PR is administered topically at a concentration ranging from about 0.05 mg / mL to about 30 mg / mL. Therefore, the ADPR described herein is administered topically at a concentration ranging from about 1 mg / mL to about 20 mg / mL.

[0117] RNA virus-associated disease or condition (e.g., HRSV-associated disease or condition), herpesvirus a disease or condition associated with Sirt6 deficiency (e.g., HSV-1-associated disease or condition), is a pathology, disease or condition that can be treated, managed, or prevented by increasing Sirt6 activity conditions, diseases or conditions associated with p53 deficiency, or treatable by increasing p53 activity, ADPR or its pharmaceutical products for the treatment, management, or prevention of a treatable or preventable disease or condition commercially acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, if The suitability of the polymorphs may be confirmed by using the assays described herein. For example, RNA viruses (e.g., HRSV) or herpes viruses (e.g., HSV-1) can be used. Infection with HIV can be confirmed by viral culture, antigen detection tests, or polymerase chain reaction tests. and can be diagnosed.

[0118] 5.6 Pharmaceutical Compositions Provided herein are methods for treating an RNA virus-associated disease or condition (e.g., HRSV-associated disease). or condition), herpes virus-associated disease or condition (e.g., HSV-1-associated disease or condition) , diseases or conditions associated with Sirt6 deficiency, treatable and manageable by increasing Sirt6 activity a disease or condition that can be prevented, a disease or condition associated with Pax6 deficiency, a disease or condition that can be prevented by increasing Pax6 activity, diseases or conditions that can be treated, managed, or prevented by administering a disease or condition, or a disease that can be treated, managed, or prevented by increasing p53 activity ADPR, or a pharmaceutically acceptable salt thereof, effective in treating, managing, or preventing a disease or condition. salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs thereof. It is a pharmaceutical composition comprising:

[0119] In some embodiments, the pharmaceutical composition is useful for treating or preventing an HRSV-associated disease or condition. In some embodiments, the pharmaceutical compositions are used to treat or inhibit HSV-1-associated diseases or conditions. In some embodiments, the pharmaceutical composition is effective in preventing a disease associated with Sirt6 deficiency. or a condition or disease that can be treated, managed, or prevented by increasing Sirt6 activity. In some embodiments, the pharmaceutical composition is useful for treating or preventing a Pax6-deficient condition. or a disease or condition associated with Pax6 loss or treatable, manageable, or capable of increasing Pax6 activity. In some embodiments, the pharmaceutical composition is useful for treating or preventing a preventable disease or condition. The composition can treat diseases or conditions associated with p53 deficiency or by increasing p53 activity. The compounds are useful in the treatment or prevention of treatable or preventable diseases or conditions.

[0120] The pharmaceutical composition may be used to prepare individual single unit dosage forms. The dosage form may be ADPR or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or steric form thereof. The pharmaceutical compositions and dosage forms of the present invention may contain isomers, isotopic species, or polymorphs. Any known or otherwise effective method for formulating or manufacturing the selected product form. For example, ADPR, or a pharmaceutically acceptable salt or solvate thereof, can be prepared by the method described above. , hydrates, tautomers, stereoisomers, isotopic species, or polymorphs are common excipients. , diluents, or carriers, and can be formulated as tablets, capsules, solutions, suspensions, emulsions, Microemulsions, nanoemulsions, syrups, elixirs, sprays, powders , aerosols (e.g., dry powder aerosols, liquid aerosols), dissolution media (e.g., acute fast-dissolving tablets, films, or strips), suppositories, ointments, or any other suitable dosage form In a specific embodiment, the pharmaceutical composition is in the form of a liquid.

[0121] Non-limiting examples of suitable excipients, diluents, or carriers include starch, sugars, mannitol, and silica. Fillers and extenders such as cellulose derivatives; carboxymethyl cellulose and other celluloses derivatives, alginates, gelatin, and binders such as polyvinylpyrrolidone; glycerol Humectants such as phosphorus; disintegrants such as calcium carbonate and sodium bicarbonate; paraffin absorption enhancers such as quaternary ammonium compounds; acetyl alcohol surfactants such as glycerol monostearate; kaolin and bentonite Adsorption carriers such as propylene glycol and ethyl alcohol; and talc. Calcium and magnesium stearate, and solid polyethylene glycol Contains lubricants.

[0122] The amounts and types of excipients, as well as the active ingredients (e.g., those disclosed herein) in the dosage form may vary. The amount and specific type of ADPR administered to a patient may include, but are not limited to: In certain embodiments, ADPR or and its pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopic forms thereof. The administration of pharmaceutical compositions or dosage forms containing the polymorphs or polymorphs can be topical, oral, parenteral, transmucosal, or transdermal. or by inhalation. As used herein, the term "parenteral" The injection can be administered intravitreally, intraocularly, intracorneally, subcutaneously, intradermally, intravenously, intraarterially, or intramuscularly. In certain embodiments, the method includes intraluminal, intraluminal, and any other similar injection or infusion technique. ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof; The isotopic species, or polymorphs, may be administered orally, for example, in a tablet, capsule, or liquid formulation. In certain embodiments, ADPR, or a pharmaceutically acceptable salt or solvate thereof, , hydrates, tautomers, stereoisomers, isotopic species, or polymorphs may be administered topically. In certain embodiments, ADPR, or a pharmaceutically acceptable salt or solvate thereof, , hydrates, tautomers, stereoisomers, isotopic species, or polymorphs may be administered intranasally or by inhalation. It can be administered intravenously.

[0123] The topical administration described herein involves administering an effective amount of ADPR, or a pharmaceutically acceptable salt thereof. Salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs may be used in combination with other compounds. These may include, but are not limited to, skin, eyes, ears, nose, sinuses, mouth, lips, pharynx, larynx, epiglottis, and trachea. , bronchi, bronchioles, alveoli, esophagus, stomach, intestines, colon, rectum, anus, vagina, cervix, and skin, of the body, including those associated with any other part of the digestive, respiratory, and / or genitourinary tracts This includes application to any mucosal and / or epithelial surface.

[0124] In addition, ADPR or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, isomers, The isomers, isotopic species, or polymorphs may be used to treat the active ingredient alone or, preferably, the specific intestinal In certain areas, preferably for extended or prolonged periods of time to further enhance effectiveness. The compound may also be formulated as a sustained or extended release dosage form, including a dosage form that releases the compound over a period of time. In this manner, the ADPRs described herein contain only the active ingredient, or preferably the active ingredient in the respiratory tract. In certain areas, preferably for extended or prolonged periods of time to further enhance effectiveness. The compositions may be formulated in sustained or extended release dosage forms, including dosage forms that release over time. Coatings, envelopes, and protective matrices in the form may be, for example, polymeric materials well known in the pharmaceutical arts. Or it can be prepared from wax.

[0125] In one embodiment, provided herein is a pharmaceutical composition comprising ADPR, wherein The amount of ADPR in the pharmaceutical composition is in the range of about 0.0001% w / w to about 100% w / w of the pharmaceutical composition. In one embodiment, the amount of ADPR in the pharmaceutical composition is about 0.0001% w / v of the pharmaceutical composition. w / w to approximately 90% w / w, approximately 0.0001% w / w to approximately 80% w / w, approximately 0.0001% w / w to approximately 70% w / w, approximately 0.0001% w / w ~approx. 60% w / w, ~approx. 0.0001% w / w~~approx. 50% w / w, ~approx. 0.0001% w / w~~approx. 40% w / w, ~approx. 0.0001% w / w about 30% w / w, about 0.0001% w / w to about 20% w / w, or about 0.0001% w / w to about 10% w / w .

[0126] In one embodiment, provided herein is a pharmaceutical composition comprising ADPR, wherein The amount of ADPR in the pharmaceutical composition is within the range of about 0.001% w / w to about 10% w / w of the pharmaceutical composition. In one embodiment, the amount of ADPR in the pharmaceutical composition is about 0.001% w / w to about 0.001% w / w of the pharmaceutical composition. Approximately 7% w / w, approximately 0.001% w / w to approximately 5% w / w, approximately 0.001% w / w to approximately 3% w / w, approximately 0.001% w / w to approximately 1% w / w , about 0.001% w / w to about 0.5% w / w, about 0.001% w / w to about 0.1% w / w, about 0.001% w / w to about 0.05% w / w , about 0.001% w / w to about 0.01% w / w, about 0.001% w / w to about 0.005% w / w, about 0.005% w / w to about 10% w / w , about 0.005% w / w to about 7% w / w, about 0.005% w / w to about 5% w / w, about 0.005% w / w to about 3% w / w, about 0.00 5% w / w to approximately 1% w / w, approximately 0.005% w / w to approximately 0.5% w / w, approximately 0.005% w / w to approximately 0.1% w / w, approximately 0.005% w / w / w to approximately 0.05% w / w, approximately 0.005% w / w to approximately 0.01% w / w, approximately 0.01% w / w to approximately 10% w / w, approximately 0.01% w / w ~approximately 7% w / w, approximately 0.01% w / w to approximately 5% w / w, approximately 0.01% w / w to approximately 3% w / w, approximately 0.01% w / w to approximately 1% w / w , about 0.01% w / w to about 0.5% w / w, about 0.01% w / w to about 0.1% w / w, about 0.01% w / w to about 0.05% w / w, about 0.05% w / w to approximately 10% w / w, approximately 0.05% w / w to approximately 7% w / w, approximately 0.05% w / w to approximately 5% w / w, approximately 0.05% w / w ~approximately 3% w / w, approximately 0.05% w / w to approximately 1% w / w, approximately 0.05% w / w to approximately 0.5% w / w, approximately 0.05% w / w to approximately 0.1% w / w, about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 7% w / w, about 0.1% w / w to about 5% w / w, about 0.1% w / w / w to about 3% w / w, about 0.1% w / w to about 1% w / w, about 0.1% w / w to about 0.5% w / w, about 0.5% w / w to about 10% w / w, about 0.5% w / w to about 7% w / w, about 0.5% w / w to about 5% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w ~ about 1% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 7% w / w, about 1% w / w to about 5% w / w, about 1% w / w / w to about 3% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 7% w / w, about 3% w / w to about 5% w / w, about 5% w / w The range is from about 10% w / w to about 10% w / w, from about 5% w / w to about 7% w / w, or from about 7% w / w to about 10% w / w.

[0127] In one embodiment, the amount of ADPR in the pharmaceutical composition is from about 0.01% w / w to about 10% w / w of the pharmaceutical composition. In one embodiment, the amount of ADPR in the pharmaceutical composition is in the range of about 0.1 wt. / wt. In another embodiment, the amount of ADPR in the pharmaceutical composition ranges from about 100 to about 2.5% w / w. It ranges from about 0.5% w / w to about 2% w / w of the pharmaceutical composition.

[0128] In certain embodiments, the pharmaceutical compositions provided herein comprise: (i) dilithium ADPR or a solvate, hydrate, tautomer, stereoisomer, isotopic species, or polymorph thereof and (ii) one or more pharmaceutically acceptable excipients; The amount of thium ADPR ranges from about 0.001% w / w to about 10% w / w of the pharmaceutical composition.

[0129] In one embodiment, provided herein are at least one anti-inflammatory drug for the eye, respiratory tract, and / or gastrointestinal tract. RNA virus or herpesvirus infection in at least one tissue, or associated with Sirt6 deficiency Suitable for topical administration to the eye, respiratory tract, and / or gastrointestinal tract, effective in the treatment and / or prevention of disorders such as wherein the pharmaceutical composition comprises ADPR, and wherein the amount of ADPR is The range is from about 0.001% w / w to about 10% w / w of the product.

[0130] In one embodiment, the prevention is prevention of infection following corneal abrasion or ocular surgery.

[0131] In one embodiment, the pharmaceutical composition is suitable for administration to the eye. In this case, pharmaceutical compositions suitable for administration to the eye further include a local anesthetic to relieve pain. In one embodiment, the local anesthetic is proparacaine, lidocaine, tetracaine, or It's a combination of those.

[0132] In one embodiment, the pharmaceutical composition is administered to tissues of the eye, respiratory tract, vagina, cervix, skin, or gastrointestinal tract. In a specific embodiment, the composition further comprises a penetration enhancer that enhances the penetration of the ADPR. The agent is a local anesthetic.

[0133] In one embodiment, the pharmaceutical composition further comprises an antimicrobial preservative. Antibacterial preservatives include sodium tetraborate, boric acid, benzalkonium chloride, and thimerosal. , chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, EDTA, sorbic acid, Onamer M, or a combination thereof. wherein the amount of antimicrobial preservative in the pharmaceutical composition is about 0.001% w / w based on the weight of the pharmaceutical composition. In a specific embodiment, the pharmaceutical composition is in the form of a solution. do.

[0134] In one embodiment, the pharmaceutical composition further comprises a co-solvent / surfactant. In this case, the co-solvents / surfactants are polysorbate 20, polysorbate 60, polysorbate 80, Pluronic F68, Pluronic F84, Pluronic P103, Cyclodextrin, Chiro In one embodiment, the co-solvent / The amount of surfactant ranges from about 0.01% w / w to about 2% w / w of the pharmaceutical composition.

[0135] In one embodiment, the pharmaceutical composition further comprises one or more viscosity enhancing agents. The thickeners are polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, Hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose cellulose, hydroxypropyl cellulose, polyethylene glycol, or a combination thereof In one embodiment, the amount of viscosity enhancing agent in the pharmaceutical composition is about 0.01% w / v of the pharmaceutical composition. In a specific embodiment, the pharmaceutical composition is in the form of a solution. do.

[0136] In one embodiment, the pharmaceutical composition is a solution, suspension, emulsion, ointment, cream, gel, or In one embodiment, the pharmaceutical composition is in the form of a liquid, suspension, or controlled release formulation. preparations, suspensions, emulsions, microemulsions, nanoemulsions, syrups, elixirs The formulation may be in the form of a powder, a dry powder, an aerosol, a liquid aerosol, a tablet, or a dissolution medium. In embodiments, the dissolution medium is a rapidly dissolving tablet, film, or strip. In an embodiment, the pharmaceutical composition is in the form of an aqueous solution.

[0137] 5.6.1 Topical Ophthalmic Preparations In certain embodiments, the pharmaceutical formulations are specifically adapted for topical application to the eye. In certain specific embodiments, disclosed herein are topical ophthalmic a pharmaceutical formulation comprising the ADPR described herein as an eye drop solution or suspension, It is prepared in a sterile, isotonic (i.e., pH of about 3 to about 8), optionally further containing a preservative and / or a viscosity enhancing agent. It is generally available as a solution of about 4 to about 8, about 7 to about 8, or about 7.4.

[0138] As used herein, the term "eye drops" refers to liquids administered in the form of drops to the outer surface of the eye. and the posterior segment of the eye, including the choroid, retinal pigment epithelium, retina, macula, fovea, optic nerve, and vitreous humor. 1 shows a medicinal liquid formulation having a local effect.

[0139] Thus, in certain embodiments, the present invention provides a method for the preparation of a medicament comprising an ADPR as described herein. The pharmaceutical formulations provided herein may be formulated using purified water and maintained at physiological pH and isotonicity. Examples of buffers for maintaining or adjusting pH include, but are not limited to: Examples of buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Examples of tonicity adjusters are sodium chloride, mannitol and glycerin.

[0140] The eye drop formulation is then optionally packaged in a plurality of individual sterile disposable cartridges, each Each of the tablets is aliquoted into suitable unit doses or packaged in a single cartridge for unit dosing. Such a single disposable cartridge may, for example, be provided at one end of the container. A container having a side wall that can be squeezed radially along a longitudinal axis to dispense the container contents from the container. Such a disposable container may be a conical or cylindrical dispenser with a specific volume. The container can be used to dispense eye drops at 0.3 to 0.4 mL per unit dose, and It is ideally suited for delivery.

[0141] Ophthalmic eye drop solutions or suspensions are often sold in various containers, e.g. as plastic bottles with eye droppers. It may also be packaged in multi-dose form. Such formulations have the advantage of preventing microbial contamination after opening the container. Preservatives are optionally added to prevent foodborne illness. Suitable preservatives include, but are not limited to, tetrahydrofuran ... Sodium phosphate, boric acid, benzalkonium chloride, thimerosal, chlorobutanol, Chilparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other materials known to those skilled in the art, and All of these are contemplated for use in the present invention. Preservative-containing formulations contain about 0.001 May contain up to about 1.0% w / v preservative.

[0142] In certain embodiments, the viscosity of the vehicle is increased, thereby reducing the angular velocity of the solution or suspension. Polymers are added to ophthalmic solutions or suspensions to prolong membrane contact and enhance bioavailability. In certain embodiments, such polymers may be added as cellulose derivatives ( For example, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose cellulose or carboxymethylcellulose), dextran 70, gelatin, polyols, Glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, polyvinyl alcohol and povidone, or a combination thereof are selected.

[0143] In certain embodiments, the ophthalmic solutions or suspensions disclosed herein contain cyclode It may further comprise a stabilizer / solubilizer such as kistrin. In the above, cyclodextrins are α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, -Cyclodextrin, Hydroxypropyl-β-cyclodextrin, Hydroxypropyl Dimethyl-γ-cyclodextrin, dimethyl-β-cyclodextrin and dimethyl-γ-cyclodextrin The compound is selected from the group consisting of quinoxin and quinoxin.

[0144] In certain embodiments, the ADPR-containing compositions described herein, such as pharmaceutical preparations comprising the ADPR described herein, are used. The pharmaceutical formulations disclosed therein may be administered in sustained release ophthalmic solution or suspension formulations.

[0145] In certain embodiments, the ADPR-containing compositions described herein, such as pharmaceutical preparations comprising the ADPR described herein, are used. The pharmaceutical formulations disclosed herein may be formulated with nanoparticles, nanoparticles, or other suitable materials to sustain drug levels at the desired location. Based on micelles, liposomes, microemulsions, bioadhesive gels and fibrin sealants Ocular drug delivery methods such as, but not limited to, colloidal dosage forms. Other ocular drug delivery systems can be formulated for administration via drug-eluting systems. Contact lenses, ultrasound-mediated drug delivery, ocular iontophoresis, and drug coatings It includes microneedles.

[0146] In certain embodiments, the frequency of administration can vary widely depending on the needs of each subject and Depending on the severity of the disease being treated, such administration may be once every 6 months, once every 5 months, once every 4 months, or Once per month, once per three months, once per two months, once per month, once per three weeks, once per two weeks , once a week, once every 6 days, once every 5 days, once every 4 days, once every 3 days, once every 2 days, or May occur once a day.

[0147] In certain embodiments, the frequency of administration will depend on the needs of each subject and the severity of the disease being treated. Depending on the severity of the condition, such administration can vary widely, from about three times a week to about three times a day, or can be from about once a week to about 10 times a day, such as once or twice a day.

[0148] 5.6.2 Preparations for nasal administration or for inhalation In certain embodiments, the pharmaceutical compositions provided herein are administered intranasally or The pharmaceutical composition is administered by inhalation into the respiratory tract. (such as a nebulizer that uses electrohydrodynamics to create an atomized mist), or inhalation For delivery using a syringe, either alone or with 1,1,1,2-tetrafluoroethane or 1,1,1, In combination with a suitable propellant such as 2,3,3,3-heptafluoropropane, it can be used as an aerosol or The pharmaceutical composition may be provided in the form of a solution, either alone or in the form of a mixture of sugars such as lactose or phospholipids. In combination with an inert carrier, as a dry powder for insufflation; and as nasal drops For nasal use, the powder may contain chitosan or cyclodextrin. It may include a bioadhesive.

[0149] Solutions or suspensions for use in pressurized containers, pumps, sprays, nebulizers, or inhalers may be used in combination with ethanol to disperse, solubilize, or extend the release of the active ingredients provided herein. alcohol, ethanol, water, or suitable substitute; propellant as solvent; and / or sorbitan Formulated to include surfactants such as trioleate, oleic acid, or oligolactic acid It can be made into

[0150] The pharmaceutical compositions provided herein may have a particle size of about 50 μm or less, or about 10 μm or less. The particles may be micronized to a size suitable for delivery by inhalation. Lattice jet milling, fluidized bed jet milling, supercritical fluid jet milling for nanoparticle formation Comminution methods known to those skilled in the art, such as boundary fluid processing, high pressure homogenization, or spray drying. It can be prepared using the method.

[0151] Capsules, blisters for use in inhalers or insufflators and the cartridge contains a powder mix of the pharmaceutical composition provided herein; lactose or a suitable powder base such as starch; and l-leucine, mannitol, or magnesium stearate. May be formulated to contain performance modifiers such as nesium. Other suitable excipients or carriers include, but are not limited to, the following: However, dextran, glucose, maltose, sorbitol, xylitol, fructooligosaccharides, For inhaled / intranasal administration, the term "sugars" as used herein includes sugars, sucrose, and trehalose. The provided pharmaceutical compositions may further comprise suitable flavorings such as menthol and levomenthol. The composition may contain a bar, and / or sweeteners such as saccharin and sodium saccharin.

[0152] 5.6.3 Oral Formulations Pharmaceutical compositions suitable for oral administration include, but are not limited to, tablets (e.g., chewable Individual formulations such as tablets, caplets, capsules, and liquids (e.g., flavored syrups) Such dosage forms may contain a predetermined amount of the active ingredient. and may be prepared by methods of pharmacy well known to those skilled in the art.

[0153] The oral dosage forms provided herein can be prepared by conventional pharmaceutical compounding techniques, incorporating the active ingredient(s) in an intimate admixture. It is prepared by combining the active ingredient with at least one excipient. Depending on the form of preparation desired for administration, it may take a wide variety of forms, for example, oral liquids. Excipients suitable for use in aqueous or aerosol dosage forms include, but are not limited to, water, glycol ether, PEG-40 ... Contains liquor, oils, alcohol, flavoring agents, preservatives, and coloring agents. of excipients suitable for use in pharmaceutical forms (e.g., powders, tablets, capsules, and caplets) Examples include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, The additives include disintegrants, binders, and disintegrants.

[0154] In one embodiment, the oral dosage form is a tablet or capsule, in which case the solid excipient In another embodiment, tablets are prepared by standard aqueous or nonaqueous techniques. Such dosage forms may be prepared by any of the methods of pharmacy. Pharmaceutical compositions and dosage forms generally comprise a carrier comprising the active ingredient in a liquid carrier, a finely divided solid carrier, or both. The mixture is then uniformly and intimately mixed with the subject and, if necessary, the mixture is then formed into the desired form. It is prepared by making

[0155] For example, tablets may be prepared by compression or molding. Compressed tablets may optionally be prepared by molding. The active ingredient in a free-flowing form, such as a powder or granules, mixed with the excipient is compressed in a suitable machine. It can be prepared by condensation.

[0156] Examples of excipients that can be used in the oral dosage forms provided herein include, but are not limited to: In pharmaceutical compositions and dosage forms, the ingredients include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use include, but are not limited to, corn starch, potato starch, or Other starches, gelatin, acacia gum, sodium alginate, alginic acid, other algins Acid salts, powdered tragacanth, natural and synthetic gums such as guar gum, cellulose and its derivatives Conductors (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium (sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose starch, pregelatinized starch, hydroxypropyl methylcellulose (e.g., No. 2208, 2906, 291 0), microcrystalline cellulose, and mixtures thereof.

[0157] Suitable forms of microcrystalline cellulose include, but are not limited to, AVICEL-PH-101, AVICEL- PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC America Viscose Division, AVICEL Sales) (available from the company Marcus Hook, PA), and and mixtures thereof. A specific binder is sold as AVICEL RC-581. It is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose. Water or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM Other suitable forms of microcrystalline cellulose include, but are not limited to, PROSOLV 50, PROSOL Silicided microcrystalline ceramics, such as those sold as PROSOLV V 90, PROSOLV HD90, and PROSOLV 90 LM, and mixtures thereof.

[0158] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms provided herein include: These include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline selenite, Cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sol In one embodiment, the pharmaceutical composition includes sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the composition is present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[0159] In certain embodiments, fillers include, but are not limited to, ethylene oxide and Such block copolymers may include block copolymers of propylene oxide and propylene oxide. Polymers may be sold as POLOXAMER or PLURONIC, and include, but are not limited to, P OLOXAMER 188 NF, POLOXAMER 237 NF, POLOXAMER 338 NF, POLOXAMER 437 NF, and It includes mixtures of these.

[0160] In certain embodiments, bulking agents include, but are not limited to, isomalt, lactose, Lactitol, mannitol, sorbitol, xylitol, erythritol, and the like It may include a mixture of these.

[0161] Disintegrants are present in the composition to provide a tablet that disintegrates when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage, while tablets containing too little disintegrant may disintegrate during storage. Tablets containing the active ingredient may not disintegrate at a desired rate or under desired conditions. A sufficient amount of disintegrant, but not too much and not too little, to adversely alter the release of the solid The amount of disintegrant used will depend on the type of formulation. In one embodiment, the pharmaceutical composition of the present invention is The composition comprises about 0.5 to about 15% by weight of disintegrant, or about 1 to about 5% by weight of disintegrant.

[0162] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agarose. Agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium , povidone, crospovidone, polacrilin potassium, sodium starch glycolate, Potato or tapioca starch, other starches, pregelatinized starch, other starches, clay, other algins, etc. The term "celluloses" includes celluloses, gums, and mixtures thereof.

[0163] Glidants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, sorbitol, PEG-40 ... Calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitan ethanol, mannitol, polyethylene glycol, other glycols, stearic acid, humectant Sodium stearyl phosphate, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., drop oils), cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil Contains zinc tearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional glidants include, for example, syloid silica gel (AEROSIL 200, (W.R. Grace, Baltimore, IL), and aerosol of coagulated synthetic silica (Texas (commercially available from Degussa Corporation of Plano, OH), CAB-O-SIL (commercially available from Degussa Corporation of Boston, MA) pyrogenic colloidal silicon dioxide products sold by Cabot Corporation), and mixtures thereof If used, the glidant may be a compound that is compatible with the pharmaceutical formulation into which it is incorporated. They may be used in an amount of less than about 1 weight percent of the pharmaceutical composition or dosage form.

[0164] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, and the like. Liquid dosage forms include solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms contain For example, water or other solvents, solubilizers, as well as ethyl alcohol, isopropyl alcohol , ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol ethanol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil) oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuryl alcohol emulsifiers such as polyethylene glycol, and sorbitan fatty acid esters, and The solvent may contain an inert diluent commonly used in the art, such as a mixture of the above.

[0165] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and the like. Adjuvants such as colorants, flavors, and preservatives may also be included.

[0166] The suspension may contain, in addition to the active inhibitor, e.g., ethoxylated isostearyl alcohol, polyisoprene, Polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxylated Aluminum, bentonite, agar agar and tragacanth, and mixtures thereof The composition may contain suspending agents such as: [Example]

[0167] 6. Working Example 6.1 Example 1: Inhibition of HRSV Replication by Li2-ADPR in A549 Cells (Drug preparation and handling): 250 mg of Li2-ADPR in powder form is placed in one glass vial. On the day of the experiment, Li2-ADPR was placed in an autoclave and stored at -20°C in the dark until use. Dissolve in 1 ml of distilled and deionized water to a concentration of 250 mg / ml. -ADPR was added to the virus growth medium (DMEM, 2.5% fetal bovine serum, and antibiotics) at a target concentration of 2.7 m It was further diluted to 0.9 mg / ml, 0.3 mg / ml, and 0.1 mg / ml.

[0168] (Inoculation and treatment): RSV encoding the Renilla luciferase reporter gene A549 cells were cultured in 96-well plates for 37 min using 250 pfu (plaque-forming units) of 10 ... The inoculum was then inoculated into a 1000 ml tube containing the target concentration of Li2-ADPR as described above. The cells were replaced with 200 μl of fresh virus growth medium and incubated at 37°C. Fresh medium containing the drug concentrations was added to the remaining samples every day. At 24 and 48 hours post-infection, cells The cells were lysed and assayed using the manufacturer's Renilla Luciferase assay system. The samples were assayed for luciferase as described by the manufacturer (Promega). The plates were transferred to a 96-well solid black plate and luminescence was measured using a PE Wallac Victor 2 1420-012 system. Quantification was performed using a stem microplate reader. Assays were performed in triplicate. The data were plotted using GraphPad Prism software.

[0169] Conclusion: Li2-ADPR was able to inhibit RSV replication in A549 cells. The effect was dose-dependent, with the highest drug concentration (2.7 mg / ml; ~5-fold difference) used. The greatest inhibition of RSV replication was observed at the lowest drug concentration (0.1 mg). / ml; ~2-fold difference).

[0170] 6.2 Example 2: Reduction of HRSV Cell Infection by Li2-ADPR in A549 Cells (Image): 250 pfu (plaque) of RSV encoding the green fluorescent protein reporter gene. -forming units) and seeding A549 cells in 96-well plates as in Example 1 (above). Images were taken daily at the same time points. Brightfield and fluorescent images were taken with an EVOS fl AMG digital microscope. Images were taken using an inverted hologram microscope at 10x magnification, and infected cells were counted.

[0171] (Conclusion): Li2-ADPR significantly reduced the percentage of A549 cells infected with HRSV. This effect was , in a dose-dependent manner, when the highest drug concentration (2.7 mg / ml; ~85% reduction) was used. The greatest reduction in HRSV infection was observed at the lowest drug concentration (0.1 mg / m l; ~50% reduction) was also observed.

[0172] 6.3 Example 3: Reduction of HRSV Cell Infection by Li2-ADPR in Primary Human Airway Epithelial Cells (Drug preparation and handling): 250 mg of Li2-ADPR in powder form is placed in one glass vial. The Li2-ADPR was autoclaved and stored at -20°C in the dark until use. The solution was dissolved in 1 ml of distilled and deionized water to a concentration of 250 mg / ml. In virus growth medium (DMEM, 2.5% fetal bovine serum and antibiotics), target concentrations of 2.7 mg / ml and 0 It was further diluted to 0.9 mg / ml.

[0173] (Inoculation and treatment): RSV encoding the Renilla luciferase reporter gene 250 pfu (plaque-forming units) of 1000 ng / ml ... After 2 hours, the inoculum was removed and fresh PBS containing the above concentrations of Li2-ADPR was added. 500 μl of HAE growth medium was added to the basement membrane side of the culture. The culture was incubated at 37°C. Fresh medium containing the target drug concentration was added to the cultures daily. Data were analyzed using Gr Plots were made using aphPad Prism software.

[0174] (Virus replication / seeding assay): At 24 and 72 hours after inoculation, the cultures were lysed and (Renilla luciferase assay system; Promega) as described by the authors. These were then plated in 96-well solid black plates and assayed for luciferase activity. The plates were transferred to a PE Wallac Victor 2 1420-012 system microplate reader and luminescence was monitored. Assays were performed in triplicate.

[0175] Conclusion: Li2-ADPR was able to significantly inhibit RSV replication in HAE cultures. This effect was dose-dependent and was observed at the highest drug concentration (2.7 mg / ml). , maximal inhibition of RSV replication was observed.

[0176] 6.4 Example 4: Plaque Inhibition of Herpes Simplex Virus Type 1 (HSV-1) KOS Strain Action of ADPR (sodium salt) (Background): 5'-Adenosine diphosphate ribose sodium salt, Sigma, in one 100 mg vial a A0752-100 mg, lot number SLBJ4805V ("sample"), was added to irrigation water at a concentration of 12 The herpesvirus plaque inhibition assay was set up on the same day. The remainder of the sample was stored in the dark at 4°C until use.

[0177] (Dilution): Dilute the sample solution 1:40 in virus growth medium to obtain an initial sample dilution of 3 mg / ml. Five additional dilutions were performed in specific virus growth media to give concentrations of 1 mg / ml, 300 μg / ml, 100 μg / ml, 30 μg / ml, and 10 μg / ml, and 6-well plates were labeled according to Table 1 .

[0178] Table 1. Sample Label [Table 1]

[0179] (Approach): Vero cells were plated in a 6-well plate at 1 × 10 5 / cm 2 After 18 hours, The growth medium was removed from each prepared cell well and 1 mL of each sample dilution was added. After incubation for 1 h, approximately 60 plaque-forming units of HSV-1 were detected per well. The virus was allowed to adsorb to the cells for 2 hours, after which the medium was removed from the monolayer. and place in herpes growth medium containing sample dilutions and agarose according to Table 1. After 3 days of incubation at 37°C, the monolayers were fixed, the agarose was removed, and The cells were stained with crystal violet and the plaques were counted.

[0180] See Table 2 for plaque counts and Figure 4 for plate images.

[0181] (Toxicity): Toxicity was assessed against the following criteria and recorded in Table 2 and on the final day of the assay. At the end of the experiment, the cells were used to evaluate the effect of dilution of the samples on the cell monolayer. 0 - No cytotoxicity Cells slightly thinner than 1-cell control wells 2 - Cells are moderately faint compared to cell control wells, and stained more intensely compared to cell control wells Moderately low intensity, viral plaques visible 3-Compared to the cell control well, the cells are very thin or there are no cells present. In comparison, the staining intensity of the cells is extremely low, and no viral plaques are visible.

[0182] (Results): At the highest sample dilution of 3 mg / ml, there was no inhibition in the number of plaques and the size of the plaques. There was a significant effect at lower concentrations, with less of an effect at lower concentrations. The monolayers were incubated with 3 mg / ml sample dilutions before fixation. This did not affect the results under a microscope, but when the agarose layer was brushed off, , and peeled off slightly brittle.

[0183] Table 2: HSV-1 plaque counts [Table 2]

[0184] (Control Drug): The control drug (acyclovir) and the concentrations used are listed in Table 2.

[0185] 6.5 Example 6.5 Sirt6 Activation by Li2-ADPR Previous studies (Pan et al., 2011, J. Biol. Chem., 286(16):14575-14587) have shown that ADPR as an entity is a mechanism by which Sirt6-dependent histone deacetylation is mediated by nicotinamide adenine dinucleotides. The dinucleotide (NAD+) and the acetyl group attached to the lysine side chain of the protein or peptide substrate They point out that it is formed during the enzymatic reaction that generates O-acetyl-ADPR from the acetyl group.

[0186] In keeping with previous findings, previous reports have shown that ADPR inhibits Sirt6 deacetylase activity at concentrations above 1 mM. It has been pointed out that the inhibitory effect is inhibited at higher concentrations than that of the control (Michishita et al., 2008, Nature, 452 (See Sirt6 assay published by Cerep / Eurofins at (7186):492-496). ADPR can inhibit the deacetylation of the related sirtuin, also known as Hst2. (Khan and Lewis, 2005, J. Biol. Chem., 281(17), 11702-11711). st2 is the yeast homologue of sirtuin 2, due to its high degree of conservation and in vitro It has been the subject of structural, mutagenesis, and kinetic studies due to its catalytic activity in vivo. In this context, Hst2 appears to play a role similar to that of Sirtuin 2.

[0187] However, in eukaryotic cells (Heiner, 2006, Biochem. J., 398(2):225-232), The concentration of bound ADPR was approximately 5 μM, and the concentration in the nucleus (Sirt6 protein is almost exclusively The amount of ATP present in the nucleus is probably quite low.

[0188] Surprisingly, in contrast to what has been described previously, ADPR at low concentrations of ≤1 μM inhibits Sirt6 This was demonstrated in two sets of tests. The first set of tests used Western blots to assess Sirt6 deacetylase activity in vitro. Using the blotting method (Rahnasto-Rilla, 2016, Methods Mol. Biol., 1436:259-269), Serially diluted concentrations of Li2-ADPR were added at 1 μg / well in 25 mM Tris-HCl (pH 8.0). of purified recombinant GST-SIRT6 protein, 2 μg of purified whole trichome chicken containing 500 μM NAD+. The cells were incubated in the presence of ATP for 30 min at 37°C. Acetylation levels were measured using anti-H3K The results were detected with 9Ac antibody and normalized to total H3 histone (Figure 5(b)). The concentrations are shown in micromoles (μM) per liter. Results (Figure 5) showed that Sirt6 deacetylase activity was significantly increased at concentrations between 0.01 and 1 μM. The activity of acetylation increased, but at concentrations above 10 μM the activity was variable. is doing.

[0189] This study was then repeated focusing on a lower range of Li2-ADPR concentrations. In this study, the ratio of H3K9Ac to total H3 (shown on the vertical axis of Figure 6 as H3K9Ac / H3) was 0.1 and 1. The second experiment, repeated three times (Figure 6), was performed at Li2-ADPR concentrations between 0.1 and 1 μM. conclusively demonstrated that it increases the ratio of Sirt6 deacetylase activity.

[0190] 6.6 Example 6.6 Sirt6 Expression Western blot was used to assess Sirt6 expression in human corneal epithelial cells.

[0191] (Cell culture): Human corneal epithelial cells (ATCC) were cultured at 37°C under 5% CO2 until slightly subconfluent (8 They were washed twice with sterile phosphate-buffered saline (PBS) and incubated at 37°C. The cells were serum-starved for 2 hours at 60 μM HCl. The serum-starvation medium was aspirated and the cells were resuspended in 60 μM HCl in serum-starvation medium. These were treated with the corresponding Li2-ADPR treatment solution at 15, 30, 60 or 12 After each time point, the treatment solution was aspirated and the cells were resuspended in cold PBS. The cells were lysed with ice-cold cell lysis buffer and incubated in an inverted position at 4°C for 30 minutes. They were then centrifuged at 14,000 g for 30 minutes at 4°C. The supernatant was collected. The total protein concentration for each sample was measured spectrophotometrically. Samples were stored frozen at -20°C until lot execution.

[0192] (Western blot): Samples were prepared in 2x Laemmli sample buffer and boiled at 95°C for 5 minutes. 20 μg of protein was loaded into each lane of an 8% Tris-glycine gel. The blots were electrophoresed at 125V for approximately 50 minutes and then transferred to nitrocellulose. 1 hour at room temperature in 3% BSA in a standard mixture of Tris-buffered saline and polysorbate 20 (TBST) After blocking, the primary antibody (anti-Sirtuin 6) was added in blocking buffer and incubated overnight at 4°C. The blot was washed three times with TBST and incubated with HRP-linked secondary antibody for 1 hour. The blot was washed again three times with TBST and then incubated with ECL reagent. Images were taken using a ChemiDocIt Imager (UVP, U) with exposures ranging from 30 seconds to 5 minutes. Image analysis was performed using VisionWorks software (UVP, Upland, CA). I went further.

[0193] Western blot results show that Sirt6 protein concentrations are consistent with baseline (no treatment lane) ) by 155% in 30 min and 1 in 60 min with 60 μM of Li2-ADPR. The results showed that Sirt6 protein levels increased by 35% for up to 2 hours. The results are shown in Figure 7.

[0194] 6.7 Example 6.7 Expression of Pax6 and Cytokeratin 12 (Cell culture): Using a method similar to that described for Sirt6 expression, Pax6 and cytochrome P450 cells were cultured. Keratin 12 expression was evaluated in human corneal epithelial cells (ATCC). The cells were incubated at 37°C under 5% CO2. These were grown to slightly subconfluent (80-90%) in sterile phosphate-buffered saline. The cells were washed twice with PBS and serum-starved at 37°C for 2 hours. The cells were treated with 60 μM of the corresponding Li2-ADPR treatment in serum-starved medium. The cells were incubated with the physiological solution for either 15, 30, 60, or 120 minutes. After each time point, The treatment solution was aspirated, and the cells were washed twice with ice-cold PBS. The cells were then placed in ice-cold cell lysis buffer. The mixture was then lysed by inverted rotation at 4°C for 30 minutes, and then centrifuged at 14,000g for 30 minutes at 4°C. The supernatant was collected and the total protein concentration for each sample was determined spectrophotometrically. Samples were stored frozen at -20°C until Western blot was performed.

[0195] (Western blot): Samples were prepared in 2x Laemmli sample buffer and boiled at 95°C for 5 minutes. 40 μg of protein was loaded into each lane of an 8% Tris-glycine gel. The blots were electrophoresed at 125V for approximately 50 minutes and then transferred to nitrocellulose. 1 hour at room temperature in 3% BSA in a standard mixture of Tris-buffered saline and polysorbate 20 (TBST) After blocking, the primary antibody (anti-Pax6 or anti-cytokeratin 12) was added in blocking buffer. The blot was washed three times with TBST and incubated overnight at 4°C. Secondary antibodies were added at 1:2000 for 40 minutes at room temperature. Blots were again washed three times with TBST. The cells were then exposed to ECL reagent for 1 minute. Images were taken using ChemiDocI with exposure times ranging from 30 seconds to 5 minutes. Image analysis was performed using VisionWorks software (UVP , Upland, CA).

[0196] The results of this Western blot showed that the concentration of Pax6 protein (isoforms 5a and 6) was , revealing a dramatic increase over baseline (no treatment). For Team 5a, the protein concentration was 1 μM for 30 min of incubation with 60 μM of Li2-ADPR. For isoform 6, the protein concentration increased by 88% at 1 min and by 584% at 60 min. The degree of inhibition increased to 179% after 30 min of incubation with 60 μM of Li2-ADPR and 302% after 60 min. Both isoforms decreased somewhat at 2 hours, with isoform 5a The cytokeratin 12 (C12) was also assessed. Both the monomeric and dimeric forms of cytokeratin 12 increased by 30, 40, and 50% compared to baseline. The monomeric form increased by 269% at 30 minutes, 789% at 60 minutes, and 120% at 120 minutes. The dimeric form of cytokeratin 12 was 139% at 30 minutes, 219% at 60 minutes, and The increase was 201% at 120 minutes and 201% at 120 minutes. These results are shown in Figure 8.

[0197] 6.8 Example 6.8 ADPR Inhibits MDM2, thereby Increasing p53 (Cell culture): p53 expression was measured using a method similar to that described for Sirt6 expression. The cells were grown at 37°C under 5% CO2 until just subconfluent. They were then washed twice with sterile phosphate-buffered saline (PBS) and allowed to grow until the cells were circulating (80-90%). The cells were serum-starved for 2 hours at 37°C. The serum-starvation medium was aspirated, and the cells were resuspended in serum-starvation medium. These were treated with 60 μM of the corresponding Li2-ADPR treatment solution. After each time point, the treatment solution was aspirated and the cells were incubated for either 120 min or 120 min. The cells were washed twice with ice-cold PBS. The cells were lysed with ice-cold cell lysis buffer and incubated at 4°C for 30 min. They were then centrifuged at 14,000 g for 30 minutes at 4°C. The supernatant was collected and The total protein concentration for each sample was measured using spectrophotometry. Samples were stored frozen at -20°C until run.

[0198] (Western blot): Samples were prepared in 2x Laemmli sample buffer and boiled at 95°C for 5 minutes. 20 μg of protein was loaded into each lane of an 8% Tris-glycine gel. The blots were electrophoresed at 125V for approximately 50 minutes and then transferred to nitrocellulose. 1 hour at room temperature in 3% BSA in a standard mixture of Tris-buffered saline and polysorbate 20 (TBST) After blocking, the primary antibody (anti-p53) was added in blocking buffer and incubated overnight at 4°C. The blot was washed three times with TBST and incubated with HRP-linked secondary antibody at 1:2000. The blot was washed again three times with TBST and incubated with ECL reagent for 1 minute. Images were taken using a ChemiDocIt Imager (UVP, Upland, MA) with exposures ranging from 30 seconds to 5 minutes. Image analysis was performed using VisionWorks software (UVP, Upland, CA). went.

[0199] (Results): Western blot results showed that p53 protein concentrations were significantly higher than baseline (no treatment) The protein concentration increased dramatically compared to the Li2-ADPR (lane 1). Incubation with 60 μM of α-glucan increased 313% in 15 min, 535% in 30 min, and 407% in 60 min. The results are shown in Figure 9. The results showed that ADPR increases the protein concentration of p53, resulting in increased p53 activation. Once p53 activation was clearly demonstrated, we assessed the binding of ADPR to MDM2. MDM2 is known to be a major inhibitor of p53 activation and is a purine The substances ATP (adenosine triphosphate) and ADP (adenosine diphosphate) are It has been previously published that ATP binds to MDM2 in vivo (Poyurovsky et al., 200 3, Molecular Cell, 12(4), 875-887; and Priest et al., 2010, Nucleic Acids Re Search, 38(21), 7587-7598). Analysis of ADPR binding to MDM2 was performed using EADock DSS-based protein This was performed using Swissdock, a protein-small molecule docking web service (Grosdidier et al. (2011, Nucleic Acids Research, 39(SUPPL. 2), 270-277). Publicly available Two previously developed protein models were used for docking. The first analysis was for ADPR The docking of the MDMX-RING domain heterodimer was evaluated (Linke et al., 2014). 008, Cell Death and Differentiation, 15(5), 841-848). ADPR is a protein that binds MDM2 and MDM4. The docking was successful in the cleft between the protein chains (Fig. 10(a)). The energy (energy) is -10.58 kcal / mol, which means that ADPR inhibits the activity of this heterodimer. This is consistent with the hypothesis that ADPR can activate p53. It was also shown that the protein binds at the interface between 53 (Fig. 10(b)). The protein structure is a small molecule benzophenone-3 (MDM2) that binds to p53 at its α-helical transactivation domain. It was previously developed for the analysis of diazepinedione inhibitors (Grasberger et al., 2002). 005, Journal of Medicinal Chemistry, 48(4), 909-912). ADPR interacts with these proteins. When docked, it binds at multiple sites within and around the transactivation domain The maximum ΔG (-8.511 kcal / mol) was found to be related to binding in the ring finger domain. Although this is lower than that observed in IFN-γ-glucan, this finding suggests that ADPR inhibits the action of MDM2 on p53. They further point out the possibility that

[0200] 6.9 Example 6.9 Li2-ADPR Reduces Viral Titers and Inhibits RSV Pulmonary Infection in Cotton Rats (altering cytokine responses in disease) (Methods) Consideration was given to attenuating hRSV cell infection in A549 cells and human airway epithelial cells. In vivo experiments in cotton rats were performed using RSVA2 infection. Adult male cotton rats (6-8 weeks old) were divided into groups of 4 animals each. All animals were pre-bled for collection and ear-tagged for identification. Ki 10 5 Plaque-forming units (pfu) were measured by intranasal instillation of 0.1 mL of RSV / A2. The study design is shown in the table below. [Table 3] Animals were treated twice daily by nasal inhalation of either phosphate-buffered saline or 0.5% Li2-ADPR. At each treatment, animals received 50 μL. On day 5, animals were monitored for viral lung titers and thyroid function. The animals were sacrificed for cytokine analysis. The gene expression of transforming growth factor beta (TGFβ) was analyzed by PCR. Bels were normalized to beta-actin.

[0201] Results: On day 5, RSV titers were reduced in Li2-ADPR-treated animals (FIG. 11(a)), and There was a significant decrease in TGFβ along with an increase in IFNγ (Figures 11(b) and 11(c), respectively). reference).

[0202] 6.10 Example 6.10 Plaque Inhibition of Li2-ADPR against HSV-1 in A549 Cells (effects on harm) (Background): Li2-ADPR was found to express moderate levels of both CD38 and CD157. The effect of the compound on inhibiting HSV-1 viral plaque formation in A549 cells was examined. Acyclovir was also included as a positive control.

[0203] Li2-ADPR was dissolved in water for irrigation to give a 100 mg / ml or 175 mM solution. This stock solution was used to prepare dilutions of the test samples. The following concentrations of Li2-ADPR were used: The following concentrations were evaluated: 0.1, 0.4, and 1.2 mM. Acyclovir was tested at 0.002 and 0.05 mM. An untreated control was also evaluated.

[0204] Target concentrations of samples per ml were injected in duplicate onto A549 cell monolayers in liquid virus growth medium. After 1 hour, approximately 100 plaque-forming units of the MacIntyre strain of HSV-1 were added to each monolayer. After virus adsorption, the medium was removed and the monolayer was placed on semi-solid agarose containing dilutions of each drug. The monolayers were fixed and stained with crystal violet, and the virus plates were then overlaid with PBS. The images of the test plates were submitted to the client for image analysis. .

[0205] Results: HSV1 results - No drug treatment (negative control) showed 1-size evenly spaced Wells treated with 0.05 mM acyclovir showed a monolayer of viable plaques. Wells treated with 0.002 mM acyclovir showed breakthrough plaques. They showed smaller plaques, but not as numerous or large as in the untreated wells. Wells treated with 1 mM Li2-ADPR had plaques of similar number and size to untreated wells. However, as the drug concentration increased from 0.4 mM to 1.2 mM, the number of plaques decreased, and The plaque size was also reduced. Figure 12 shows the effect of Li2-ADPR on plaque inhibition against HSV-1. It shows the effect.

[0206] The percentage of plaque area was calculated using ImageJ, version 1.52i. The results for the no treatment control are as follows: [Table 4]

[0207] Although there was some variation at 0.4 mM, as the concentration of Li2-ADPR increased, the plaque There was a clear decrease in the percentage of area. The present application provides the following aspects of the invention. (Aspect 1) A method for treating, managing, or preventing an RNA virus-associated disease or condition in a patient. The method further comprises administering an effective amount of 5'-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt thereof. any salts, solvates, hydrates, tautomers, stereoisomers, isotopic species, or polymorphs thereof administering the antibody to said patient; wherein said patient is suffering from an RNA virus-associated disease or condition. The method, wherein the subject has or is at risk of developing the disease. (Aspect 2) The RNA virus-associated disease or condition is caused by an RNA virus, wherein the RNA The virus is a Coronaviridae virus, a Pneumobilidae virus, a Paramyxoviridae virus, or Daeidae viruses, Picornaviridae viruses, or Orthomyxoviridae viruses The method of embodiment 1, wherein the (Aspect 3) The Coronaviridae virus is a coronavirus or SARS; The Paramyxoviridae virus is a human respiratory syncytial virus (HRSV); The virus is a human parainfluenza virus, a measles virus, or a mumps virus. the Picornaviridae virus is a rhinovirus, and the orthomic The method of embodiment 2, wherein the Soviridae virus is an influenza virus. (Aspect 4) The method of embodiment 2, wherein the RNA virus is a Pneumoviridae virus. (Aspect 5) The method of embodiment 2, wherein the RNA virus is HRSV. (Aspect 6) The RNA virus-associated disease or condition is an ocular disease, conjunctivitis, keratitis, keratoconjunctiv ... Membrane peeling, ulcerative infectious keratitis, superficial keratitis, interstitial keratitis, uveitis, acute glaucoma, eye Blepharitis, otitis media, otitis externa, gingivitis, mucositis, pharyngitis, tonsillitis, rhinitis, sinusitis, laryngitis, pseudomyelitis Membranous laryngitis, tracheitis, bronchitis, bronchiolitis, bronchopneumonia, pneumonia, asthma exacerbation, chronic obstructive pulmonary disease The method of embodiment 1, wherein the symptom is a pulmonary disease exacerbation, an emphysema exacerbation, or a chronic pulmonary disease exacerbation. (Aspect 7) The RNA virus-associated disease or condition is conjunctivitis, keratitis, keratoconjunctivitis, pharyngitis, tonsillitis, The method of embodiment 6, wherein the condition is laryngitis, rhinitis, sinusitis, bronchitis, bronchiolitis, or pneumonia. (Aspect 8) 8. The method of claim 7, wherein the RNA virus-associated disease or condition is keratitis, conjunctivitis, or keratoconjunctivitis. How to post. (Aspect 9) Aspect 7, wherein the RNA virus-associated disease or condition is bronchitis, bronchiolitis, or pneumonia. The method described. (Aspect 10) The RNA virus-associated disease or condition is pharyngitis, tonsillitis, sinusitis, or laryngitis. 8. The method of embodiment 7. (Aspect 11) The administration is by topical, oral, parenteral, transmucosal, or inhalation routes of administration. The method described in Example 1. (Aspect 12) The method of embodiment 1, wherein said administering is by inhalation. (Aspect 13) 12. The method of embodiment 11, wherein said local administration is to a cell or tissue surface within said patient. (Aspect 14) The topical administration can be by aerosolization, nebulization, spraying, oral delivery, intratracheal instillation, intrabronchial, or by injection into the airway surface. (Aspect 15) The method of embodiment 11, wherein said local administration is to an external cell or tissue surface. (Aspect 16) 16. The method of claim 15, wherein the external cell or tissue surface is a surface of the skin, eye, nail, hair, or ear. How to do it. (Aspect 17) The method of embodiment 1, wherein said administering is by intravenous, intraarterial, or intraductal infusion. (Aspect 18) The patient is administered ADPR or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof. , stereoisomers, isotopic species, or polymorphs, and excipients, diluents, or carriers. The method of embodiment 1, wherein the patient is administered a pharmaceutical composition comprising: (Aspect 19) The pharmaceutical composition is a liquid, a suspension, an emulsion, a microemulsion, a nanoemulsion, Suppositories, enemas, syrups, elixirs, dry powder aerosols, liquid aerosols, tablets or in the form of a dissolution medium. (Aspect 20) 20. The method of claim 19, wherein the dissolution medium is a fast dissolving tablet, film, or strip. . (Aspect 21) 20. The method of embodiment 19, wherein the pharmaceutical composition is in the form of a solution. (Aspect 22) A mode in which the ADPR or a pharmaceutical composition containing ADPR is administered in combination with other drugs. The method described in any one of methods 1 to 21. (Aspect 23) 23. The method of aspect 22, wherein the other pharmaceutical agent is an antiviral compound. (Aspect 24) The method of embodiment 1, wherein the ADPR is in the form of its sodium salt. (Aspect 25) 2. The method of embodiment 1, wherein the ADPR is in the form of its disodium salt. (Aspect 26) 2. The method of embodiment 1, wherein the ADPR is in the form of its lithium salt. (Aspect 27) 2. The method of embodiment 1, wherein said ADPR is in the form of its dilithium salt. (Aspect 28) The ADPR may comprise one or more of sodium, lithium, potassium, calcium, magnesium, 2. The method of embodiment 1, wherein the compound is in the form of a combination of zinc, cobalt, and / or copper salts. (Aspect 29) A method for increasing Sirtuin 6 (Sirt6) activity in a patient in need thereof, comprising: administering to a patient an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof; The method comprises administering a compound, stereoisomer, isotopic species, or polymorph. (Aspect 30) A method for treating, managing, or preventing a disease or condition associated with a Sirt6 deficiency in a patient. The method comprises administering to the patient an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof. This includes administering a compound, hydrate, tautomer, stereoisomer, isotopic species, or polymorph. wherein the patient has or develops a disease or condition associated with a Sirt6 deficiency. The method, wherein there is a risk of developing a disease. (Aspect 31) The disease or condition is a viral disease, an age-related disease, diabetes, type 2 diabetes, respiratory distress syndrome, or the like. Respiratory disorders, chronic lung disease, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, ocular Disease, diabetic retinopathy, retinal disease, retinal detachment, adult macular degeneration, glaucoma, liver disease, non-alcoholic beverages Collagen-related steatohepatitis, chronic hepatitis infection, neurodegenerative disorders (e.g., Alzheimer's disease), cognitive Disorders resulting in impaired function, traumatic brain or spinal cord injury, cancer, chemotherapy-induced neuropathies Neuropathy related to ischemic or traumatic events, autoimmune diseases, and excessive inflammation related disorders, pulpitis, mitochondrial diseases or disorders, cardiovascular diseases, stroke, stress-related disorders Related disorders, such as arthritis, osteoarthritis, preterm labor, and reduced cellular glycolytic activity benefit disorders caused by hypoxia or ischemia-related muscle tissue damage, blood clotting disorders, fungal infections, ischemia, chronic pain associated with a brain and / or spinal cord disease, high blood pressure, or any combination thereof; The method of embodiment 30. (Aspect 32) A method for treating, managing, or preventing a herpes virus-associated disease or condition in a patient. The method comprises administering to the patient an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof. This includes administering a compound, hydrate, tautomer, stereoisomer, isotopic species, or polymorph. wherein the patient has or develops a herpes virus-associated disease or condition. The method, wherein there is a risk of developing a disease. (Aspect 33) The herpes virus-related disease or condition is caused by herpes simplex virus type 1 (HSV1) or simplex virus type 2 (HSV3). A condition caused by a herpesvirus selected from herpesvirus type 2 (HSV2). The method described in 32. (Aspect 34) 1. A method of increasing the activity of Pax6 in a patient in need thereof, comprising administering to the patient an effective amount of ADPR of the formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof , an isotopic species, or a polymorph. (Aspect 35) A method for treating, managing, or preventing a disease or condition associated with a Pax6 deficiency in a patient. The method comprises administering to the patient an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof, including administering hydrates, tautomers, stereoisomers, isotopic species, or polymorphs. wherein the patient has or will develop a disease or condition associated with a Pax6 deficiency. The method has a risk of (Aspect 36) The disease or condition is aniridia, an ocular disease associated with aniridia, aniridia-related keratopathy, corneal ulcers, Keratoconus, uveitis, diabetic retinopathy, retinal disease, retinal detachment, acute retinal necrosis, Gillespie syndrome, Peters anomaly, WAGR syndrome, dry eye, presbyopia, myopia, glaucoma, congenital glaucoma , cataracts, corneal damage or infection, keratitis, keratoconjunctivitis, adult macular degeneration, diabetic retinopathy, Postoperative recovery from eye or brain surgery, limbal stem cell deficiency, diabetes, type 2 diabetes, neurodegenerative diseases (e.g. (e.g., Alzheimer's disease, Parkinson's disease, etc.), disorders that cause cognitive decline, cerebellar motor Ataxia, hyposmia, nystagmus, auditory processing disorder, memory impairment, autism, mental retardation, brain or spinal cord injury 35. The method of embodiment 34, wherein the injury is caused by trauma, stroke, or any combination thereof. (Aspect 37) Methods for increasing p53 levels in patients in need thereof by inhibiting MDM2 administering to the patient an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; administration of a compound, tautomer, stereoisomer, isotopic species, or polymorph How to write. (Aspect 38) A method for treating, managing, or preventing a disease or condition associated with p53 deficiency in a patient. The method comprises administering to the patient an effective amount of ADPR, or a pharmaceutically acceptable salt or solvate thereof, including administering hydrates, tautomers, stereoisomers, isotopic species, or polymorphs. wherein the patient has or will develop a disease or condition associated with a p53 deficiency. The method has a risk of (Aspect 39) The disease or condition is a viral disease, an age-related disease, diabetes, type 2 diabetes, respiratory distress syndrome, or the like. Respiratory disorders, chronic lung disease, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, ocular Disease, diabetic retinopathy, retinal disease, retinal detachment, adult macular degeneration, glaucoma, presbyopia, cataract, liver liver disease, non-alcoholic steatohepatitis, chronic hepatitis infection, neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease and Parkinson's disease), disorders resulting in cognitive decline, trauma resulting in brain or spinal cord damage , cancer, cancer secondary to viral infection, chemotherapy-induced neuropathy, ischemic or traumatic injury Neuropathies related to sexual events, autoimmune diseases, disorders related to excessive inflammation, pulpitis, Mitochondrial diseases or disorders, cardiovascular disease, stroke, stress-related disorders, arthritis , osteoarthritis, preterm labor, disorders that benefit from reduced cellular glycolytic activity, hypoxia or ischemia-related muscle tissue damage, blood clotting disorders, fungal infections, ischemia, brain and / or spinal cord disease

[0039] Aspect 37 is a chronic pain associated with hypertension, a wound healing disorder, or any combination thereof. The method described.

Claims

1. 1. A pharmaceutical composition for inhibiting MDM2, thereby increasing the concentration of p53 in a patient in need thereof, and treating, managing, or preventing a disease or condition associated with p53 deficiency in said patient, comprising 5'-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopic species, or polymorph thereof; the patient has or is at risk of developing a disease or condition associated with p53 deficiency, and The pharmaceutical composition as described above, wherein the disease or condition is diabetic retinopathy.

2. The pharmaceutical composition of claim 1, wherein the ADPR is administered by topical administration.

3. 3. The pharmaceutical composition of claim 2, wherein the local administration is to an external cell or tissue surface.

4. 3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is in the form of a solution.

5. The pharmaceutical composition of claim 1, wherein the ADPR is administered in combination with another drug.

6. 6. The pharmaceutical composition of claim 5, wherein the other pharmaceutical agent is an antiviral compound.

7. 2. The pharmaceutical composition of claim 1, wherein the ADPR is in the form of its sodium salt.

8. 10. The pharmaceutical composition of claim 1, wherein the ADPR is in the form of its disodium salt.

9. 10. The pharmaceutical composition of claim 1, wherein the ADPR is in the form of its lithium salt.

10. 10. The pharmaceutical composition of claim 1, wherein the ADPR is in the form of its dilithium salt.

11. the amount of ADPR in the pharmaceutical composition is from about 0.05% w / w to about 3% w / w of the pharmaceutical composition; and 11. The pharmaceutical composition of any one of claims 1 to 4 or 7 to 10, wherein the pharmaceutical composition is for topical administration once daily, twice daily, or three times daily.

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