Antiviral oligonucleotides

Abstract

Random sequence oligonucleotides that have antiviral activity are described, along with their use as antiviral agents. In many cases, the oligonucleotides are greater than 40 nucleotides in length and include chemical modifications, such as modified internucleotidic linkages and modifications at the 2′-position of the ribose moieties. Also described are methods for the prophylaxis or treatment of a viral infection in a human or animal, and a method for the prophylaxis treatment of cancer caused by oncoviruses in a human or animal. The methods typically involve administering to a human or animal in need of such treatment, a pharmacologically acceptable, therapeutically effective amount of at least one oligonucleotide that act by a sequence complementary mode of action.

1 . An oligonucleotide, having at least 50% of its nucleotides in said oligonucleotide modified at the 2′-position of the ribose moiety and having at least 50% of its internucleotidic linkages modified, wherein said oligonucleotide has an antiviral activity against a target virus, said activity operating predominantly by a sequence independent mode of action.  
     
     
         2 . The oligonucleotide according to  claim 1 , wherein said oligonucleotide has at least 50% of its nucleotides in said oligonucleotide modified at the 2′-position of the ribose moiety and has at least 80% of its internucleotidic linkages modified, wherein said oligonucleotide has an antiviral activity against a target virus, said activity operating predominantly by a sequence independent mode of action.  
     
     
         3 . The oligonucleotide according to  claim 1 , wherein said oligonucleotide has at least 80% of its nucleotides in said oligonucleotide modified at the 2′-position of the ribose moiety and has at least 80% of its internucleotidic linkages modified, wherein said oligonucleotide has an antiviral activity against a target virus, said activity operating predominantly by a sequence independent mode of action.  
     
     
         4 . The oligonucleotide according to  claim 1 , wherein said oligonucleotide has at least 90% of its nucleotides in said oligonucleotide modified at the 2′-position of the ribose moiety and having at least 90% of its internucleotidic linkages modified, wherein said oligonucleotide has an antiviral activity against a target virus, said activity operating predominantly by a sequence independent mode of action.  
     
     
         5 . The oligonucleotide according to  claim 1 , wherein said oligonucleotide has at least 100% of its nucleotides in said oligonucleotide modified at the 2′-position of the ribose moiety and having at least 100% of its internucleotidic linkages modified, wherein said oligonucleotide has an antiviral activity against a target virus, said activity operating predominantly by a sequence independent mode of action.  
     
     
         6 . The oligonucleotide of  claim 1 , wherein the modified linkages are selected from the group consisting of phosphorothioate linkages, phosphorodithioate linkages, and boranophosphate linkages.  
     
     
         7 . The oligonucleotide of  claim 5 , wherein the modified linkages are selected from the group consisting of phosphorothioate linkages, phosphorodithioate linkages, and boranophosphate linkages.  
     
     
         8 . The oligonucleotide of  claim 1 , wherein at least 50% of the nucleotides in said oligonucleotide comprises 2′-OMe moieties at the 2′-position of the ribose moiety.  
     
     
         9 . The oligonucleotide of  claim 5 , wherein at least 100% of the nucleotides in said oligonucleotide comprises 2′-OMe moieties at the 2′-position of the ribose moiety.  
     
     
         10 . The oligonucleotide of  claim 1 , wherein at least 50% of the nucleotides in said oligonucleotide comprise 2′-methoxyethoxy substitutions at the 2′-position of the ribose moiety.  
     
     
         11 . The oligonucleotide of  claim 5 , wherein at least 100% of the nucleotides in said oligonucleotide comprise 2′-methoxyethoxy substitutions at the 2′-position of the ribose moiety.  
     
     
         12 . The oligonucleotide of  claim 1 , wherein said oligonucleotide is at least 30 nucleotides in length.  
     
     
         13 . The oligonucleotide of  claim 1 , wherein said oligonucleotide is at least 40 nucleotides in length.  
     
     
         14 . The oligonucleotide of  claim 1 , comprising a homopolymer sequence of at least 10 contiguous nucleotides selected from the group consisting of A, T, U, C, G, and I.  
     
     
         15 . The oligonucleotide of  claim 1 , comprising a sequence of at least 10 nucleotides in length selected from the group consisting of polyAT, polyAC, polyAG, polyAU, polyAI, polyGC, polyGT, polyGU, polyGI, polyCT, polyCU, polyCI, and polyTI.  
     
     
         16 . The oligonucleotide of  claim 1 , wherein at least 15% of the nucleotides in said oligonucleotide comprise 2′-methoxyethoxy or 2′OMe substitutions at the 2′-position of the ribose moiety.  
     
     
         17 . The oligonucleotide of  claim 1 , wherein said oligonucleotide is a concatemer consisting of two or more oligonucleotide sequences joined by a linker.  
     
     
         18 . The oligonucleotide of  claim 1 , wherein said oligonucleotide is linked or conjugated at one or more nucleotide residues, to a molecule modifying the characteristics of the oligonucleotide to obtain one or more characteristics selected from the group consisting of higher stability, lower serum interaction, higher cellular uptake, higher viral protein interaction, an improved ability to be formulated for delivery, a detectable signal, higher antiviral activity, better pharmacokinetic properties, specific tissue distribution, lower toxicity.  
     
     
         19 . The oligonucleotide of  claim 1 , wherein said oligonucleotide is double stranded.  
     
     
         20 . The oligonucleotide of  claim 1 , wherein said oligonucleotide targets a DNA virus or a RNA virus.  
     
     
         21 . The oligonucleotide of  claim 1 , wherein said oligonucleotide targets a member of the group consisting of herpesviridae, HSV-1, HSV-2, CMV Varicella Zoster Virus, Epstein Barr Virus, Human Herpesvirus 6A and 6B, hepadnaviridae, HBV, parvoviridae, poxviridae, papillomaviridae, adenoviridae, retroviridae, HIV-1, HIV-2, paramyxoviridae, RSV, parainfluenza virus, human metapneumovirus, bunyaviridae, hantavirus, Rift Valley fever virus, Crimean Congo Hemorrhagic Fever virus, picornaviridae, coxsackievirus, rhinovirus, flaviviridae, yellow fever virus, dengue virus, West Nile virus, hepatitis C virus, filoviridae, Ebola virus, Marburg virus, orthomyxoviridae, influenza virus, togaviridae, Western Equine Encephalitis virus, coronaviridae, reoviridae rhabdoviridae, arenaviridae, lassa fever virus and calciviridae.  
     
     
         22 . An oligonucleotide as set forth in any one of REP 1001, REP 2001, REP 3007, REP 2004, REP 2005, REP 2006, REP 2007, REP 2008, REP 2017, REP 2018, REP 2020, REP 2021, REP 2024, REP 2036, A20, G20, C20, REP 2029, REP 2031, REP 2030, REP 2033, REP 2055, REP 2056, REP 2057, REP 2060 and REP 2107.  
     
     
         23 . An oligonucleotide mixture comprising a mixture of at least two different antiviral oligonucleotides of  claim 1 .  
     
     
         24 . An oligonucleotide mixture comprising a mixture of at least ten different antiviral oligonucleotides of  claim 1 .  
     
     
         25 . An antiviral pharmaceutical composition comprising 
 a therapeutically effective amount of at least one pharmacologically acceptable, antiviral oligonucleotide as defined in  claim 1;  and    a pharmaceutically acceptable carrier.    
     
     
         26 . A kit comprising at least one antiviral oligonucleotide as defined in  claim 1 , in a labeled package, wherein the antiviral activity of said oligonucleotide occurs principally by a non-sequence complementary mode of action and the label on said package indicates that said antiviral oligonucleotide can be used against at least one virus.  
     
     
         27 . The kit of  claim 26 , wherein said kit contains a mixture of at least two different antiviral oligonucleotides.  
     
     
         28 . A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide as defined in  claim 1 .  
     
     
         29 . A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide mixture as defined in  claim 23 .  
     
     
         30 . A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable antiviral pharmaceutical composition as defined in  claim 25 .  
     
     
         31 . A method for the prophylactic treatment of cancer caused by oncoviruses in a human or a non-human animal, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide as defined in  claim 1 .  
     
     
         32 . A method for the prophylactic treatment of cancer caused by oncoviruses in a human or a non-human animal, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide mixture as defined in  claim 23 .  
     
     
         33 . A method for the prophylactic treatment of cancer caused by oncoviruses in a human or a non-human animal, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable antiviral pharmaceutical composition as defined in  claim 25 .  
     
     
         34 . An antiviral pharmaceutical composition comprising a therapeutically effective amount of at least one pharmacologically acceptable, polypyrimidine oligonucleotide and a pharmaceutically acceptable carrier, wherein the antiviral activity of said oligonucleotide occurs principally by a sequence independent mode of action.  
     
     
         35 . The antiviral pharmaceutical composition of  claim 34 , wherein the oligonucleotide comprises at least one modified internucleotidic linkage.  
     
     
         36 . The composition of  claim 34 , wherein said composition is formulated for administration to an acidic in vivo site.  
     
     
         37 . The composition of  claim 34 , wherein said composition is adapted for oral, vaginal, or topical administration.  
     
     
         38 . The composition of  claim 34 , wherein said composition comprises at least one polyC oligonucleotide.  
     
     
         39 . The composition of  claim 34 , wherein said composition comprises at least one polyT oligonucleotide.  
     
     
         40 . The composition of  claim 34 , wherein said composition comprises at least one polyCT oligonucleotide.  
     
     
         41 . A method for the prophylaxis or treatment of a viral infection in an acidic environnement in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable antiviral pharmaceutical composition as defined in  claim 34 , said composition being adapted for administration to an acidic in vivo site.  
     
     
         42 . An oligonucleotide, having at least 50% of its internucleotidic linkages modified, wherein said oligonucleotide has an antiviral activity against a target virus, said activity operating predominantly by a sequence independent mode of action, said oligonucleotide comprising at least 80% of pyrimidine residues.  
     
     
         43 . The oligonucleotide of  claim 42 , wherein said oligonucleotide has at least 80% of its internucleotidic linkages modified.  
     
     
         44 . The oligonucleotide of  claim 42 , wherein said oligonucleotide has at least 80% of its internucleotidic linkages modified and has 100% of pyrimidine residues.  
     
     
         45 . The oligonucleotide of  claim 42 , wherein said oligonucleotide has 100% of its internucleotidic linkages modified and has at least 80% of pyrimidine residues.  
     
     
         46 . The oligonucleotide of  claim 42 , wherein said oligonucleotide has 100% of its internucleotidic linkages modified and has 100% of pyrimidine residues.  
     
     
         47 . The oligonucleotide of  claim 42 , wherein the modified linkages are selected from the group consisting of phosphorothioate linkages, phosphorodithioate linkages, and boranophosphate linkages.  
     
     
         48 . The oligonucleotide of  claim 46 , wherein the modified linkages are selected from the group consisting of phosphorothioate linkages, phosphorodithioate linkages, and boranophosphate linkages.  
     
     
         49 . The oligonucleotide of  claim 42 , wherein the modified linkages are phosphorothioate linkages  
     
     
         50 . The oligonucleotide of  claim 48 , wherein the modified linkages are phosphorothioate linkages.  
     
     
         51 . The oligonucleotide of  claim 42 , wherein the pyrimidine residues are cytosine residues.  
     
     
         52 . The oligonucleotide of  claim 46 , wherein the pyrimidine residues are cytosine residues.  
     
     
         53 . The oligonucleotide of  claim 42 , wherein the pyrimidine residues are thymine residues.  
     
     
         54 . The oligonucleotide of  claim 46 , wherein the pyrimidine residues are thymine residues.  
     
     
         55 . The oligonucleotide of  claim 42 , wherein the pyrimidine residues are cytosine or thymine residues.  
     
     
         56 . The oligonucleotide of  claim 46 , wherein the pyrimidine residues are cytosine or thymine residues.  
     
     
         57 . The oligonucleotide of  claim 42 , wherein said oligonucleotide is at least 30 nucleotides in length.  
     
     
         58 . The oligonucleotide of  claim 46 , wherein said oligonucleotide is at least 30 nucleotides in length.  
     
     
         59 . The oligonucleotide of  claim 42 , wherein said oligonucleotide is at least 40 nucleotides in length.  
     
     
         60 . The oligonucleotide of  claim 46 , wherein said oligonucleotide is at least 40 nucleotides in length.  
     
     
         61 . The oligonucleotide of  claim 42 , wherein at least 15% of the nucleotides in said oligonucleotide comprise 2′-methoxyethoxy or 2′-OMe substitutions at the 2′-position of the ribose moiety.  
     
     
         62 . The oligonucleotide of  claim 42 , wherein said oligonucleotide is a concatemer consisting of two or more oligonucleotide sequences joined by a linker.  
     
     
         63 . The oligonucleotide of  claim 46 , wherein said oligonucleotide is a concatemer consisting of two or more oligonucleotide sequences joined by a linker.  
     
     
         64 . The oligonucleotide of  claim 42 , wherein said oligonucleotide is linked or conjugated at one or more nucleotide residues, to a molecule modifying the characteristics of the oligonucleotide to obtain one or more characteristics selected from the group consisting of higher stability, lower serum interaction, higher cellular uptake, higher viral protein interaction, an improved ability to be formulated for delivery, a detectable signal, higher antiviral activity, better pharmacokinetic properties, specific tissue distribution, lower toxicity.  
     
     
         65 . The oligonucleotide of  claim 46 , wherein said oligonucleotide is linked or conjugated at one or more nucleotide residues, to a molecule modifying the characteristics of the oligonucleotide to obtain one or more characteristics selected from the group consisting of higher stability, lower serum interaction, higher cellular uptake, higher viral protein interaction, an improved ability to be formulated for delivery, a detectable signal, higher antiviral activity, better pharmacokinetic properties, specific tissue distribution, lower toxicity.  
     
     
         66 . The oligonucleotide of  claim 42 , wherein said oligonucleotide is double stranded.  
     
     
         67 . The oligonucleotide of  claim 46 , wherein said oligonucleotide is double stranded.  
     
     
         68 . The oligonucleotide of  claim 42 , wherein said oligonucleotide targets a DNA virus or a RNA virus.  
     
     
         69 . The oligonucleotide of  claim 46 , wherein said oligonucleotide targets a DNA virus or a RNA virus.  
     
     
         70 . The oligonucleotide of  claim 42 , wherein said oligonucleotide targets a member of the group consisting of herpesviridae, HSV-1, HSV-2, CMV Varicella Zoster Virus, Epstein Barr Virus, Human Herpesvirus 6A and 6B, hepadnaviridae, HBV, parvoviridae, poxviridae, papillomaviridae, adenoviridae, retroviridae, HIV-1, HIV-2, paramyxoviridae, RSV, parainfluenza virus, human metapneumovirus, bunyaviridae, hantavirus, Rift Valley fever virus, Crimean Congo Hemorrhagic Fever virus, picornaviridae, coxsackievirus, rhinovirus, flaviviridae, yellow fever virus, dengue virus, West Nile virus, hepatitis C virus, filoviridae, Ebola virus, Marburg virus, orthomyxoviridae, influenza virus, togaviridae, Western Equine Encephalitis virus, coronaviridae, reoviridae rhabdoviridae, arenaviridae, lassa fever virus and calciviridae.  
     
     
         71 . The oligonucleotide of  claim 46 , wherein said oligonucleotide targets a member of the group consisting of herpesviridae, HSV-1, HSV-2, CMV Varicella Zoster Virus, Epstein Barr Virus, Human Herpesvirus 6A and 6B, hepadnaviridae, HBV, parvoviridae, poxviridae, papillomaviridae, adenoviridae, retroviridae, HIV-1, HIV-2, paramyxoviridae, RSV, parainfluenza virus, human metapneumovirus, bunyaviridae, hantavirus, Rift Valley fever virus, Crimean Congo Hemorrhagic Fever virus, picornaviridae, coxsackievirus, rhinovirus, flaviviridae, yellow fever virus, dengue virus, West Nile virus, hepatitis C virus, filoviridae, Ebola virus, Marburg virus, orthomyxoviridae, influenza virus, togaviridae, Western Equine Encephalitis virus, coronaviridae, reoviridae rhabdoviridae, arenaviridae, lassa fever virus and calciviridae.  
     
     
         72 . An oligonucleotide mixture comprising a mixture of at least two different antiviral oligonucleotides of  claim 42 .  
     
     
         73 . An oligonucleotide mixture comprising a mixture of at least two different antiviral oligonucleotides of  claim 46 .  
     
     
         74 . An oligonucleotide mixture comprising a mixture of at least ten different antiviral oligonucleotides of  claim 42 .  
     
     
         75 . An oligonucleotide mixture comprising a mixture of at least ten different antiviral oligonucleotides of  claim 46 .  
     
     
         76 . An antiviral pharmaceutical composition comprising 
 a therapeutically effective amount of at least one pharmacologically acceptable, antiviral oligonucleotide as defined in  claim 42;  and    a pharmaceutically acceptable carrier.    
     
     
         77 . An antiviral pharmaceutical composition comprising 
 a therapeutically effective amount of at least one pharmacologically acceptable, antiviral oligonucleotide as defined in  claim 46;  and    a pharmaceutically acceptable carrier.    
     
     
         78 . The composition of  claim 76 , wherein said composition is formulated for administration to an acidic in vivo site.  
     
     
         79 . The composition of  claim 77 , wherein said composition is formulated for administration to an acidic in vivo site.  
     
     
         80 . The composition of  claim 76 , wherein said composition is adapted for oral, vaginal, or topical administration.  
     
     
         81 . The composition of  claim 77 , wherein said composition is adapted for oral, vaginal, or topical administration.  
     
     
         82 . A kit comprising at least one antiviral oligonucleotide as defined in  claim 42 , in a labeled package, wherein the antiviral activity of said oligonucleotide occurs principally by a non-sequence complementary mode of action and the label on said package indicates that said antiviral oligonucleotide can be used against at least one virus.  
     
     
         83 . A kit comprising at least one antiviral oligonucleotide as defined in  claim 46 , in a labeled package, wherein the antiviral activity of said oligonucleotide occurs principally by a non-sequence complementary mode of action and the label on said package indicates that said antiviral oligonucleotide can be used against at least one virus.  
     
     
         84 . The kit of  claim 78 , wherein said kit contains a mixture of at least two different antiviral oligonucleotides.  
     
     
         85 . The kit of  claim 83 , wherein said kit contains a mixture of at least two different antiviral oligonucleotides.  
     
     
         86 . A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide as defined in  claim 42 .  
     
     
         87 . A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide as defined in  claim 46 .  
     
     
         88 . A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide mixture as defined in  claim 72 .  
     
     
         89 . A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide mixture as defined in  claim 73 .  
     
     
         90 . A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable antiviral pharmaceutical composition as defined in  claim 76 .  
     
     
         91 . A method for the prophylaxis or treatment of a viral infection in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable antiviral pharmaceutical composition as defined in  claim 77 .  
     
     
         92 . A method for the prophylactic treatment of cancer caused by oncoviruses in a human or a non-human animal, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide as defined in  claim 42 .  
     
     
         93 . A method for the prophylactic treatment of cancer caused by oncoviruses in a human or a non-human animal, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide as defined in  claim 46 .  
     
     
         94 . A method for the prophylactic treatment of cancer caused by oncoviruses in a human or a non-human animal, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide mixture as defined in  claim 72 .  
     
     
         95 . A method for the prophylactic treatment of cancer caused by oncoviruses in a human or a non-human animal, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable oligonucleotide mixture as defined in  claim 73 .  
     
     
         96 . A method for the prophylactic treatment of cancer caused by oncoviruses in a human or a non-human animal, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable antiviral pharmaceutical composition as defined in  claim 76 .  
     
     
         97 . A method for the prophylactic treatment of cancer caused by oncoviruses in a human or a non-human animal, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable antiviral pharmaceutical composition as defined in  claim 77 .  
     
     
         98 . An antiviral pharmaceutical composition comprising a therapeutically effective amount of at least one pharmacologically acceptable, polypyrimidine oligonucleotide and a pharmaceutically acceptable carrier, wherein the antiviral activity of said oligonucleotide occurs principally by a sequence independent mode of action; and a pharmaceutically acceptable carrier.  
     
     
         99 . The antiviral pharmaceutical composition of  claim 98 , wherein the oligonucleotide comprises modified internucleotidic linkages.  
     
     
         100 . The composition of  claim 98 , wherein said composition is formulated for administration to an acidic in vivo site.  
     
     
         101 . The composition of  claim 98 , wherein said composition is in the form of a powder.  
     
     
         102 . The composition of  claim 98 , wherein said composition is adapted for oral, vaginal, or topical administration.  
     
     
         103 . The composition of  claim 98 , wherein said composition comprises at least one polyC oligonucleotide.  
     
     
         104 . The composition of  claim 98 , wherein said composition comprises at least one polyT oligonucleotide.  
     
     
         105 . The composition of  claim 98 , wherein said composition comprises at least one polyCT oligonucleotide.  
     
     
         106 . A method for the prophylaxis or treatment of a viral infection in an acidic environnement in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable antiviral pharmaceutical composition as defined in  claim 42 , said composition being adapted for administration to an acidic in vivo site.  
     
     
         107 . A method for the prophylaxis or treatment of a viral infection in an acidic environnement in a subject, comprising administering to a subject in need of such a treatment a therapeutically effective amount of at least one pharmacologically acceptable antiviral pharmaceutical composition as defined in  claim 46 , said composition being adapted for administration to an acidic in vivo site.