Methods of screening for SCAP antagonists

Abstract

The invention relates to a method for screening therapeutic agents, defined as SCAP antagonists, for use in combating diseases associated with elevated lipid levels, said method comprising detecting or assaying the extent or result of transcriptional activity or binding between a control SCAP antagonist and SCAP, in the presence of and absence of said agent. Also claimed are therapeuic agents which are antagonists of SCAP, identified by such a method and their use in combating diseases associated with elevated lipid levels.

1 . A method for screening agents which bind to SCAP in a way which has the opposite effect to cholesterol and its metabolites by promoting the activation of the SCAP/SREBP pathway (SCAP antagonists), for use in combating diseases associated with elevated circulating levels of LDL-cholesterol and/or triglycerides, said method comprising detecting or assaying the extent or result of transcriptional activity or binding competition on SCAP between a test SCAP antagonist and a control SCAP antagonist, or between a test SCAP antagonist and cholesterol, or a metabolite thereof.  
     
     
         2 . A method according to  claim 1  which involves a binding assay whereby the binding between SCAP and a labelled control SCAP antagonist, in the presence of a test SCAP antagonist, with that in the absence of said test SCAP antagonist, is compared.  
     
     
         3 . A method according to  claim 1  which involves a functional assay whereby the extent of activation of the SREBP pathway is determined in the presence of a test SCAP antagonist, and then confirming that the effect is mediated by antagonising the effect of cholesterol bound to SCAP by comparing the binding between SCAP and a labelled control SCAP antagonist, in the presence of a test SCAP antagonist, with that in the absence of said test SCAP antagonist.  
     
     
         4 . A method according to  claim 3  where the functional assay comprises determination of the extent of transcriptional activation of the LDL-receptor promoter in HepG2 cells.  
     
     
         5 . A SCAP antagonist, identified by a method according to any one of claims  1 - 4 , or a physiologically acceptable salt, solvate or derivative thereof.  
     
     
         6 . A pharmaceutical composition comprising a compound according to  claim 5 , or a physiologically acceptable salt, solvate or derivative thereof, together with one or more pharmaceutically acceptable carriers.  
     
     
         7 . A method for the treatment of a mammal, including man, of conditions resulting from elevated circulating levels of LDL-cholesterol and/or triglycerides, comprising administration of an effective amount of a SCAP antagonist, or a physiologically acceptable salt, solvate or derivative thereof.  
     
     
         8 . A method according to  claim 7  where the condition is selected from atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), coronary heart diseases and obesity.  
     
     
         9 . A method for identifying compounds which will be useful in for the treatment of conditions resulting from elevated circulating levels of LDL-cholesterol and/or triglycerides comprising the step of determining whether the compound interacts directly with SCAP.  
     
     
         10 . A method for the treatment of conditions resulting from elevated circulating levels of LDL-cholesterol and/or triglycerides comprising administration of a compound which may be identified according to the method of  claim 9.