Methods of Identifying Compounds that Modulate IL-4 Receptor-Mediated IgE Synthesis Utilizing a B-Cell Associated Protein

Abstract

The present provides compounds capable of modulating IL-4 receptor-mediated IgE production, as well as IL-4 induced processes associated therewith, methods and kits for identifying such compounds that utilize a BAP-37 as a surrogate analyte and methods of using the compounds in a variety of in vitro, in vitro and ex vivo contexts.

1 . A compound comprising a peptide or peptide analog, or a pharmaceutically acceptable salt thereof, having the formula (I): 
         Z 1 -X 1 ˜X 2 ˜X 3 ˜X 4 ˜X 5 ˜X 6 ˜X 7 ˜X 8 ˜X 9 ˜X 10 ˜X 11 ˜X 12 ˜X 13 ˜X 14 ˜X 15 ˜X 16 ˜X 17 ˜X 18 ˜X 19 ˜X 20 ˜Z 2   
       wherein: 
 X 1  is a hydroxyl-containing residue or a small polar residue;  
 X 2  is an aliphatic residue;  
 X 3  is an aliphatic residue;  
 X 4  is an aromatic residue or an Ala residue;  
 X 5  is an aliphatic residue;  
 X 6  is an acidic residue or an Ala residue;  
 X 7  is an aliphatic residue;  
 X 8  is a polar residue;  
 X 9  is an aliphatic residue;  
 X 10  is a polar residue or an Ala residue;  
 X 11  is a basic residue or an Ala residue;  
 X 12  is a hydroxyl-containing residue or a small polar residue;  
 X 13  is an aliphatic residue;  
 X 14  is a non-polar residue;  
 X 15  is an aromatic residue or an Ala residue;  
 X 16  is an aromatic residue or an Ala residue;  
 X 17  is an aliphatic residue;  
 X 18  is a hydroxyl-containing residue or a small polar residue;  
 X 19  is a hydroxyl-containing residue or a small polar residue;  
 X 20  is a non-polar residue or a structurally-constrained residue;  
 Z 1  is RRN—, RC(O)NR—, RS(O) 2 NR— or an amino-terminal blocking group;  
 Z 2  is —C(O)OR, —C(O)O—, —C(O)NRR or a carboxyl-terminal blocking group;  
 each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;  
 each “˜” independently represents an amide, a substituted amide or an isostere of an amide;  
 each “-” represents a bond, or a 1 to 10 residue peptide or peptide analog; and  
 wherein one or more of X 1 , X 2 , X 19 , or X 20  may be absent.  
 
     
     
         2 . The compound of  claim 1  in which each “˜” is an amide, Z 1  is H 2 N— and Z 2  is —C(O)OH or —C(O)O − .  
     
     
         3 . The compound of  claim 1  having the formula: 
         T G X 3  X 4  V V E L Q I X 10  X 11  S I M H Y I S S P 
       wherein: 
 X 3  is an aliphatic residue;  
 X 4  is an aromatic residue or an Ala residue;  
 X 10  is a polar residue or an Ala residue; and  
 X 11  is a basic residue or an Ala residue.  
 
     
     
         4 . The compound of  claim 3  in which X 3  is V or A and/or X 4  is H or A.  
     
     
         5 . The compound of  claim 3  in which X 10  is N or A and/or X 11  is R or A.  
     
     
         6 . The compound of  claim 1  which is selected from the group consisting of CL08wt (SEQ ID NO:1), CL08NR (SEQ ID NO:2), CL08VH (SEQ ID NO:3) CL08EL (SEQ ID NO: 4), CL08HY (SEQ ID NO: 5) and an analog thereof.  
     
     
         7 . A compound comprising a peptide or peptide analog having the formula (IV) 
         Z 1 -T˜G˜V˜H˜V˜E˜L˜Q˜I˜N˜R˜S˜I˜M˜H˜Y˜I˜S˜S˜P-Z 2   (IV) 
       wherein: 
 Z 1  is RRN—, RC(O)NR—, RS(O) 2 NR— or an amino-terminal blocking group;  
 Z 2  is —C(O)OR, —C(O)O—, —C(O)NRR or a carboxyl-terminal blocking group;  
 each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;  
 each “˜” independently represents an amide, a substituted amide or an isostere of an amide; and  
 each “-” represents a bond, or a 1 to 10 residue peptide or peptide analog;  
 and variants thereof in which 1, 2, 3 or 4 of the amino acid residues set forth in IV are replaced by another amino acid selected from the same class as the original amino acid or by an Ala residue.  
 
     
     
         8 . A compound that modulates IL-4 receptor-mediated IgE production, comprising determining whether the compound binds a B-cell associated protein-37 (BAP 37), wherein the ability to bind the BAP-37 identifies the compound as being a modulator of IL-4 induced IgE production.  
     
     
         9 . A pharmaceutical composition comprising a compound according to  claim 1  or  claim 3 , and a pharmaceutically acceptable carrier, excipient or diluent.  
     
     
         10 . A pharmaceutical composition comprising a compound identified by the method of  claim 8  and a pharmaceutically acceptable carrier, excipient or diluent.