Env polypeptide complexes and methods of use

Abstract

Provided herein are small molecule CD4 mimetics effective to bind to HIV Env proteins. A CD4 mimetic of the invention, when bound to an Env protein, is effective to induce a conformational change in the Env protein such that cyptic epitopes on the Env protein are exposed. Also provided herein are related methods of identifying and using such small molecule CD4 mimetics, for example, to elicit an immune response in a subject upon administration.

1 . A method of eliciting an immune response in a subject, the method comprising administering to the an Env polypeptide and a CD4 mimetic, wherein the Env protein and CD4 mimetic are administered simultaneously, sequentially in any order, separately, or as a complex, and wherein the CD4 mimetic is selected from the group consisting of {1-[(4,6-dimethyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}(4-fluorophenyl)methanone and ethyl 1-[(4,6-dimethyl-1H-indol-2-yl)carbonyl]piperidine-4-carboxylate. 
     
     
         2 . The method of  claim 1 , wherein the Env polypeptide and the CD4 mimetic are administered intravenously, intramuscularly or subcutaneously. 
     
     
         3 . The method of  claim 1 , wherein the immune response is a cellular production of antibodies to CD41. 
     
     
         4 . The method of  claim 1 , wherein the Env polypeptide is a gp120 polypeptide. 
     
     
         6 . The method of  claim 1 , wherein the small molecule CD4 mimetic is {1-[(4,6-dimethyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}(4-fluorophenyl)methanone. 
     
     
         7 . The method of  claim 1 , wherein the small molecule CD4 mimetic is ethyl 1-[(4,6-dimethyl-1H-indol-2-yl)carbonyl]piperidine-4-carboxylate. 
     
     
         8 . A method of producing an antibody that binds to a cryptic epitope of an Env polypeptide, the method comprising administering an Env polypeptide and a CD4 mimetic, wherein the Env protein and CD4 mimetic, wherein the CD4 mimetic is selected from the group consisting of {1-[(4,6-dimethyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}(4-fluorophenyl)methanone and ethyl 1-[(4,6-dimethyl-1H-indol-2-yl)carbonyl]piperidine-4-carboxylate under conditions effective to form antibodies in the subject. 
     
     
         9 . The method of  claim 8 , further comprising the step of isolating the antibodies formed by the subject. 
     
     
         10 . The method of  claim 8 , wherein the antibodies formed are neutralizing antibodies. 
     
     
         11 . The method of  claim 8 , wherein the antibodies formed are monoclonal antibodies. 
     
     
         12 . The method of  claim 8 , wherein the antibodies are polyclonal antibodies. 
     
     
         13 . The method of  claim 8 , wherein the Env polypeptide is a gp120 polypeptide. 
     
     
         14 . The method of  claim 8 , wherein the small molecule CD4 mimetic is {1-[(4,6-dimethyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}(4-fluorophenyl)methanone. 
     
     
         15 . The method of  claim 8 , wherein the small molecule CD4 mimetic is ethyl 1-[(4,6-dimethyl-1H-indol-2-yl)carbonyl]piperidine-4-carboxylate.