Inhibitors of Retroviral Replication

Abstract

Methods for preventing or treating retroviral infection, such as human immunodeficiency virus, in vivo utilize transcriptional inhibitory compounds. These include cortistatin A and analogs of the cortistatin family.

1 . A method of preventing viral infection or treating a viral infection in a patient, comprising:
 administering to the patient a therapeutically effective amount of an inhibitor of retroviral transcription wherein the inhibitor inhibits retroviral transcription as compared to a control; and,   preventing viral infection or treating a viral infection in the patient,   wherein the inhibitor of retroviral transcription comprises cortistatins, cortistatin derivatives, analogs, substituted cortistatins or salts thereof.   
     
     
         2 . The method of  claim 1 , wherein the retroviral viral infection is a lentivirus. 
     
     
         3 . The method of  claim 2 , wherein the lentivirus is a human immunodeficiency virus (HIV). 
     
     
         4 . The method of  claim 1 , wherein the inhibitor of retroviral transcription inhibits function or activity of a Trans-Activator of Transcription (Tat), a molecule associated with Trans-Activator of Transcription (Tat), a molecule associated with Transactivation Responsive element (TAR) a Transactivation Responsive element (TAR) and/or interaction between a Trans-Activator of Transcription (Tat) and a Transactivation Responsive element (TAR), DNA-PK or combinations thereof. 
     
     
         5 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the inhibitor of retroviral transcription comprises a cortistatin agent having a general structure of Formula XII: 
       
         
           
           
               
               
           
         
         Wherein: 
         R 1  is hydrido (H), a straight chain, branched chain or cyclic alkyl, alkenyl, or alkynyl moiety, an aromatic, heterocyclic or alicyclic moiety that contains one to about 24 carbon atoms, in which a heterocyclic moiety contains 1 to four rings that each contain up to four ring atoms other than carbon that can be oxygen, nitrogen or sulfur; 
         R 5  is hydrido (H), a straight chain, branched chain or cyclic alkyl, alkenyl, or alkynyl moiety, an aromatic, heterocyclic or alicyclic moiety that contains one to about 24 carbon atoms, in which a heterocyclic moiety contains 1 to four rings that each contain up to four ring atoms other than carbon that can be oxygen, nitrogen or sulfur; and the circled X is a cyclic or heterocyclic substituent that contains 4 to about 15 carbon atoms, contains one to three saturated or unsaturated rings and up to three atoms per ring that are other than carbon and can be oxygen, nitrogen or sulfur. 
       
     
     
         13 . The method of  claim 1 , wherein the inhibitor of retroviral transcription comprises a cortistatin agent having a general structure of Formula XIII: 
       
         
           
           
               
               
           
         
         Wherein: 
         R 1  is hydrido (H), a straight chain, branched chain or cyclic alkyl, alkenyl, or alkynyl moiety, an aromatic, heterocyclic or alicyclic moiety that contains one to about 24 carbon atoms, in which a heterocyclic moiety contains 1 to four rings that each contain up to four ring atoms other than carbon that can be oxygen, nitrogen or sulfur; 
         R 5  is hydrido (H), a straight chain, branched chain or cyclic alkyl, alkenyl, or alkynyl moiety, an aromatic, heterocyclic or alicyclic moiety that contains one to about 24 carbon atoms, in which a heterocyclic moiety contains 1 to four rings that each contain up to four ring atoms other than carbon that can be oxygen, nitrogen or sulfur; and the circled X is a cyclic or heterocyclic substituent that contains 4 to about 15 carbon atoms, contains one to three saturated or unsaturated rings and up to three atoms per ring that are other than carbon and can be oxygen, nitrogen or sulfur; with the proviso that R 1  and R 5  are not both methyl when the circled X group is a 7-isoquinoline. 
       
     
     
         14 . The method of claim of  claim 1 , wherein the cortistatin analog is a didehydro-cortistatin A (dCA). 
     
     
         15 . The method of  claim 1 , wherein the cortistatin is cortistatin A. 
     
     
         16 . The method of  claim 1 , further comprising administering to a patient therapeutically effective amount of one or more anti-retroviral drugs. 
     
     
         17 . The method of  claim 16 , wherein the antiviral drugs comprise one more of: fusion inhibitors (FIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), protease inhibitors (PIs) or integrase inhibitors (INIs). 
     
     
         18 . A method of inhibiting retroviral production in vitro or in vivo comprising: contacting a cell or administering to a patient an effective amount of an inhibitor of retroviral replication; and modulating retroviral replication in vitro or in vivo, wherein the inhibitor of retroviral transcription comprises cortistatins cortistatin derivatives, analogs, substituted cortistatins or salts thereof. 
     
     
         19 . The method of  claim 18 , wherein the retrovirus is a human immunodeficiency virus (HIV). 
     
     
         20 . The method of  claim 18 , wherein the inhibitor of retroviral transcription inhibits function or activity of a Trans-Activator of Transcription (Tat), a molecule associated with Trans-Activator of Transcription (Tat), a molecule associated with Transactivation Responsive element (TAR) a Transactivation Responsive element (TAR) and/or interaction between a Trans-Activator of Transcription (Tat) and a Transactivation Responsive element (TAR), DNA-PK or combinations thereof. 
     
     
         21 . The method of  claim 18 , optionally comprising contacting a cell or administering to a patient infected with a retrovirus a therapeutically effective amount of one or more anti-retroviral drugs. 
     
     
         22 . The method of  claim 21 , wherein the anti-retroviral drugs comprise one more of: fusion inhibitors (FIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), protease inhibitors (PIs) or imegrase inhibitors (INIs). 
     
     
         23 . (canceled) 
     
     
         24 . The method of claim of  claim 18 , wherein the cortistatin analog is a didehydro-cortistatin A (dCA). 
     
     
         25 . The method of  claim 18 , wherein the cortistatin is cortistatin A. 
     
     
         26 . A method of modulating function or activity of a human immunodeficiency virus (HIV) transcriptional promoter in vitro or in vivo comprising:
 administering a therapeutically effective amount of an agent which modulates function or activity of a Trans-Activator of Transcription (Tat), a molecule associated with Trans-Activator of Transcription (Tat), a molecule associated with Transactivation Responsive element (TAR) a Transactivation Responsive element (TAR) and/or interaction between a Trans-Activator of Transcription (Tat) and a Transactivation Responsive element (TAR), or DNA-PK; and,   modulating function or activity of a human immunodeficiency virus (HIV) transcriptional promoter in vitro or in vivo.   
     
     
         27 . The method of  claim 26 , wherein the agent comprises cortistatin, cortistatin derivatives, analogs, substituted cortistatins or salts thereof. 
     
     
         28 . A pharmaceutical composition comprising: cortistatins, cortistatin derivatives, analogs, substituted cortistatins or salts thereof. 
     
     
         29 . (canceled)