Methods of Identifying Compounds that Modulate IL-4 Receptor-Mediated IgE Synthesis Utilizing an Adenosine Kinase

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 an adenosine kinase as a surrogate analyte and methods of using the compounds in a variety of in vitro, in vitro and ex vivo contexts.

1 - 24 . (canceled)  
     
     
         25 . 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 ˜X 21 ˜X 22 ˜X 23 -Z 2    wherein: 
 X 1  is an acidic residue;  
 X 2  is a hydroxyl-containing residue;  
 X 3  is a non-polar residue;  
 X 4  is a polar residue;  
 X 5  is an aliphatic residue;  
 X 6  is a polar residue;  
 X 7  is a cysteine-like residue;  
 X 8  is an aliphatic residue;  
 X 9  is an aliphatic residue;  
 X 10  is cysteine-like residue or an aliphatic residue;  
 X 11  is a basic residue or an aliphatic residue;  
 X 12  is a hydroxyl-containing residue, a small polar residue or an aliphatic residue;  
 X 13  is an aliphatic residue;  
 X 14  is an aromatic residue;  
 X 15  is an aliphatic residue;  
 X 16  is an aliphatic residue;  
 X 17  is an aliphatic residue;  
 X 18  is an aromatic residue;  
 X 19  is an aromatic residue;  
 X 20  is an acidic residue;  
 X 21  is an aliphatic residue;  
 X 22  is an aliphatic residue;  
 X 23  is a conformationally-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 22 , or X 23  may be absent.  
   
     
     
         26 . The compound of  claim 25  in which each “˜” is an amide, Z 1  is H 2 N— and Z 2  is —C(O)OH or —C(O)O − .  
     
     
         27 . The compound of  claim 25  having the formula (II):  
         D T M Q V Q C G X 9  X 10  X 11  X 12  G Y V V A F W D V G P  
       wherein: 
 X 9  is a small aliphatic residue;  
 X 10  is a cysteine-like residue or Gly;  
 X 11  is a basic residue or a small aliphatic residue; and  
 X 12  is a small hydroxyl-containing residue or a small aliphatic residue.  
 
     
     
         28 . The compound of  claim 27  in which X 9  is V or A and/or X 10  is C or G.  
     
     
         29 . The compound of  claim 27  in which X 11  is R or A and/or X 12  is S or G.  
     
     
         30 . The compound of  claim 25  which is selected from the group consisting of AR02E8wt (SEQ ID NO:1), AR02E8VC (SEQ ID NO:2), AR02E8RS (SEQ ID NO:3) and an analog thereof.  
     
     
         31 . A compound comprising a peptide or peptide analog having the formula (IV)  
         Z 1 -D˜T˜M˜Q˜V˜Q˜C˜G˜V˜C˜R˜S˜G˜Y˜V˜V˜A˜F˜W˜D˜V˜G˜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 one or two 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 or a Gly residue.    
     
     
         32 . A compound identified by the method of claim  1 .  
     
     
         33 . A pharmaceutical composition comprising a compound according to  claim 25  or  claim 31 , and a pharmaceutically acceptable carrier, excipient or diluent.  
     
     
         34 . A pharmaceutical composition comprising a compound identified by the method of claim  1  and a pharmaceutically acceptable carrier, excipient or diluent.  
     
     
         35 - 52 . (canceled)