Compounds and methods for the inhibition of protein-protein interactions

Abstract

Compounds having molecular weights of less than 1500 daltons that non-covalently interact with target proteins and covalently bond to target proteins at amino acid side chains that are not part of enzyme active sites, in which covalently bound portions of the compounds sterically block the binding of the target proteins to other proteins, are disclosed. The compounds react with forward reaction rates at least 100 times faster than the forward reaction rates at which the compounds bond to the side chains of the corresponding free amino acids under physiological conditions. Compositions including these compounds and methods for preparing these compounds are also disclosed.

What is claimed is:  
     
         1 . A method of producing a compound that selectively binds to a target protein, said method comprising 
 (a) providing a candidate compound having a molecular weight of less than 1500 daltons and comprising a first group and a second group, wherein said second group covalently bonds to an amino acid side chain of said target protein and said first group does not covalently bond to any amino acid side chain;    (b) testing said candidate compound for inhibition of the interaction of said target protein and a second protein;    (c) testing said candidate compound for binding to a non-target molecule;    (d) testing said candidate compound for bonding reactivity of said second group with said amino acid side chain of said target protein;    (e) altering said first group and selecting for increased selectivity for said target protein, wherein increased selectivity is indicated by an increase in the inhibition of the interaction of the target protein and said second protein, relative to said binding to said non-target molecule;    (f) altering said second group and selecting for decreased bonding reactivity of said second group with said amino acid side chain of said target protein and with the non-target molecule; and    (g) optionally repeating steps (e) and (f), whereby a compound is obtained that has a selectivity for the target protein, relative to the non-target molecule, that is at least 100 times greater than said candidate compound of step (a).    
     
     
         2 . The method of  claim 1 , wherein said compound selectively binds to said target protein at an amino acid side chain that is not part of an enzyme active site, and wherein said compound binds to said target protein at a site of protein-protein interaction.  
     
     
         3 . The method of  claim 1 , wherein said candidate compound is present in or chosen from a combinatorial chemistry library.  
     
     
         4 . The method of  claim 1 , wherein said first group is a Specificity Group that non-covalently binds to said protein under physiological conditions, and said second group is a Bonding Group that forms a covalent bond with said amino acid side chain on said protein, wherein modification of said Specificity Group does not substantially alter the reactivity of said Bonding Group.  
     
     
         5 . The method of  claim 1 , wherein said candidate compound of step (a) is the compound of  claim 1 .  
     
     
         6 . A method of producing a compound that selectively binds to a target protein, said method comprising 
 (a) providing a candidate compound having a molecular weight of less than 1500 daltons and comprising a first group and a second group, wherein said second group covalently bonds to an amino acid side chain of said target protein and said first group does not covalently bond to any amino acid side chain;    (b) testing said candidate compound for inhibition of the interaction of said target protein and a second protein;    (c) testing said candidate compound for binding to a non-target molecule;    (d) testing said candidate compound for bonding reactivity of said second group with said amino acid side chain of said target protein;    (e) altering said first group and selecting for increased selectivity for said target protein, wherein increased selectivity is indicated by an increase in the inhibition of the interaction of the target protein and said second protein, relative to said binding to said non-target molecule;    (f) altering said second group and selecting for decreased bonding reactivity of said second group with said amino acid side chain of said target protein and with the non-target molecule; and    (g) optionally repeating steps (e) and (f), whereby a compound is obtained that has a selectivity for the target protein, relative to the non-target molecule, that is at least 100 times greater than said candidate compound of step (a), wherein said compound has a covalent bonding rate with the side chain of the corresponding free amino acid of less than 10 −5 /M/sec at room temperature under physiological conditions.    
     
     
         7 . The method of  claim 6 , wherein said compound selectively binds to said target protein at an amino acid side chain that is not part of an enzyme active site, and wherein said compound binds to said target protein at a site of protein-protein interaction.