Use of agent for suppressing infection and proliferation of human immunodeficiency syndrome virus

Abstract

The present invention relates to agent for suppressing infection and proliferation of human immunodeficiency syndrome virus (HIV-1), which infects immunocompetent cells such as macrophage or dendritic cell and causes destruction of immune system, and use of known compounds, macrolide derivatives for suppression of infection and proliferation of human immunodeficiency syndrome virus in M type macrophage derived from human monocytes. The present invention is useful for treatment of patients with HIV-1 infection by low cost chemotherapeutic agents, and in addition, is clinically used as supplement agent in HAART.

1 . A method for suppressing infection and/or proliferation of human immunodeficiency syndrome virus in a macrophage derived from a human monocyte, comprising treating said macrophage with an effective amount of a macrolide derivative selected from oxacyclotetradecane-2,10-dione,4((2,6-dideoxy-3-0-methyl-α-L-ribo-hexopyranosyl)oxy]-14-ethyl-7,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-6-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy; 11-(1′-hydroxy-propyl)-3-[2,6-dideoxy-3-C-methyl-α-L-ribo-hexopyranosyl]oxy]-5-[(3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl)oxy]-2,4,6,8,11,14-hexamethyl-10,13,15-tri-oxatricyclo[9.2.1.1. 9.6 ]-pentadecane-1-one; 6,15,16-Trioxatricyclo[10.2.1.11,4]hexadecane, erythromycin derivative; 4,13-Dioxabicyclo[8.2.1]tridec-12-en-5-one,7-[2,6-dideoxy-3-C-methyl-α-L-ribo-hexopyranosyl)oxy]-3-(1,2-dihydroxy-1-methylbutyl)-2,6,8,10,12-pentamethyl-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hyxopyranosyl]oxy]; Oxacyclo-tetradecane-2,10-dione,4-[2,6-dideoxy-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-6-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]; de(3′-N-methyl)-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; de(3′-N-methyl)-3′-N-sulfonyl-8,9-anhydro-pseudo-erythromycin A 6,9-hemiketal or salt thereof; de(3′-N-methyl)-[3′-N-(3-hydroxy-1-propyl)]-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; de(3′-N-methyl)-3′-N-(2-acetoxyethyl)-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; de(3′-N-methyl)-3′-N-cyanomethyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; de(3′-N-methyl)-3′-N-(2-fluoroethyl)-8,9-anhydro-pseudo-erythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′-N-ethyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′,3′-N,N-diethyl-8,9-anhydro-pseudo erythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′-N-allyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′,3′-N,N-diallyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′-N-propargyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′,3′-N,N-dipropargyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′-N-propyl-8,9-anhydro-pseudo-erythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′,3′-N,N-dipropyl-8,9-anhydro-pseudo-erythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′-N-hexyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′,3′-N,N-dihexyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′-N-benzyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′,3′-N,N-dibenzyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′-N-(2-propyl)-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′,3′-N,N-di-(10-bromo-1-decanyl)-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; bis-de(3′-N-methyl)-3′-N-acetyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; de(3′-dimethylamino)-3′-piperidino-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; de(3′-dimethylamino)-3′-pyrrolidino-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; de(3′-dimethylamino)-3′-morpholino-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; de(3′-dimethylamino)-3′-[hexahydro-1(1H)-azepinyl]-8,9-anhydro-pseudo-erythromycin A 6,9-hemiketal or salt thereof; de(12-hydroxy)-de[12-(1-hydroxypropyl)]-12-hydroxyoxime-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; de[12-(hydroxypropyl)]-8,9-anhydro-pseudoerythromycin A 6,9 -hemiketal or salt thereof; de(12-hydroxy)-de[12-(1-hydroxypropyl)]-12-amino-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; de(3′-N-methyl)-de[12-(1-hydroxypropyl)]-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof; de(3-O-cladinosyl)-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof and de(3-O-cladinosyl)-de(3′-N-methyl)-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal or salt thereof.  
     
     
         2 . The method according to  claim 1 , wherein the macrophage derived from human monocytes is an M type M macrophage.  
     
     
         3 . The method according to  claim 1 , wherein the macrolide derivative suppresses the proliferation of the virus by suppressing expression of tyrosine kinase Hck protein and activation of p38MAPK in M type M macrophage.  
     
     
         4 . The method according to  claim 1 , wherein said macrophage is in a subject being, or who has been, treated with highly active anti-retroviral therapy (HAART).  
     
     
         5 . The method according to  claim 1 , wherein said macrophage is in vitro.  
     
     
         6 . The method according to  claim 2 , wherein the macrolide derivative suppresses the proliferation of the virus by suppressing expression of tyrosine kinase Hck protein and activation of p38MAPK in M type M macrophage.  
     
     
         7 . The method according to  claim 2 , wherein said macrophage is in a subject being, or who has been, treated with highly active anti-retroviral therapy (HAART).  
     
     
         8 . The method according to  claim 3 , wherein said macrophage is in a subject being, or who has been, treated with highly active anti-retroviral therapy (HAART).  
     
     
         9 . The method according to  claim 5 , wherein the macrophage derived from human monocytes is an M type M macrophage.  
     
     
         10 . The method according to  claim 2 , wherein the macrolide derivative suppresses the proliferation of the virus by suppressing expression of tyrosine kinase Hck protein and activation of p38MAPK in M type M macrophage.  
     
     
         11 . The method according to  claim 4 , wherein the macrolide derivative suppresses the proliferation of the virus by suppressing expression of tyrosine kinase Hck protein and activation of p38MAPK in M type M macrophage.