Anti-picornaviral ligands via a combinatorial computational and synthetic approach

Abstract

The present invention provides structure-based combinatorial libraries of compounds containing the functional group minima of picornaviruses including poliovirus and rhinovirus. The libraries can be used to screen for therapeutical antiviral compounds, e.g., anti-picornaviral capsid-binding compounds.

What is claimed is:  
     
         1 . A composition comprising a mixture of reaction products resulting from a combinational synthesis of two aromatic monomers and a spacer monomer, wherein the two aromatic monomers are covalently linked through X to the spacer monomer, X is S or  0 , the aromatic monomer and the spacer monomer are functional group minima of a picornavirus.  
     
     
         2 . The composition according to  claim 1  wherein the aromatic monomer and the spacer monomer are functional group minima of poliovirus.  
     
     
         3 . The composition according to  claim 1  wherein the aromatic monomer and the spacer monomer are functional group minima of rhinovirus.  
     
     
         4 . The composition according to  claim 1  wherein the two aromatic monomers are selected from the group consisting of a single five or six membered rings and fused double rings comprising a five membered ring and a six membered ring or two six membered rings and wherein one of the rings contains a hydroxyl group substituent or a sulfhydryl group substituent.  
     
     
         5 . The composition according to  claim 1  wherein the spacer monomer is a symmetric bis- (bromo methyl) arene or alkene.  
     
     
         6 . The compositions according to  claim 1  wherein the spacer monomer is a bis (chloro methyl) arene or alkene.  
     
     
         7 . The compositions according to  claim 1  wherein the spacer monomer is a bis (iodo methyl) arene or alkene.  
     
     
         8 . The compositions according to  claim 1  wherein the spacer monomer is a bis (tosyl) arene or alkene.  
     
     
         9 . The composition according to  claim 1  wherein the aromatic monomer contains a sulfyhydryl group substituent and the spacer monomer is an α, ω dibromo alkane.  
     
     
         10 . The composition according to  claim 1  wherein the aromatic monomer contains a sulfyhydryl group substituent and the spacer monomer is an α, ω dichloro alkane.  
     
     
         11 . The composition according to  claim 1  wherein the aromatic monomer contains a sulfyhydryl group substituent and the spacer monomer is an α, ω
 diido alkane.  
 
     
     
         12 . The composition according to  claim 4  wherein the aromatic monomer containing the sulfyhydryl or hydroxyl substituent has one or more additional substituents on the ring whereby the additional substituents are less electophillic than the spacer monomers, e.g., these additional substituents may be hydroxyl, sulfhydryl, methoxy, ester, nitro or halogens (such as fluro, chloro, bromo, iodo groups).  
     
     
         13 . The composition according to  claim 4  wherein the structures with the hydroxyl group may contain heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen.  
     
     
         14 . The composition according to  claim 12  wherein the ring structures with the hydroxyl group may contain heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen.  
     
     
         15 . The composition according to  claim 4  wherein the ring structures with the sulfhydryl group may contain heroatoms selected from the group consisting of nitrogen and oxygen.  
     
     
         16 . The composition according to  claim 12  wherein the ring structures with the hydroxyl group may contain heteroatoms selected from the group consisting of nitrogen and oxygen.  
     
     
         17 . The composition according to  claim 4  wherein the spacer monomer is linked to the aromatic ring structures by a sulfur or oxygen atom.  
     
     
         18 . A library comprising functional group minima of picornaviruses covalently linked such that aromatic functional groups are linked via linker functional groups and wherein the aromatic functional groups are selected from the group consisting of a single five or six membered rings and fused double rings comprising a five membered ring and a six membered ring or two six membered rings and wherein one of the rings contains a hydroxyl group substituent or a sulfhydryl group substituent.  
     
     
         19 . The library according to  claim 18  wherein the spacer monomer is a symmetric bis-(bromo methyl) arene or alkene.  
     
     
         20 . The library according to  claim 18  wherein the spacer monomer is a bis (chloro methyl) arene or alkene.  
     
     
         21 . The library according to  claim 18  wherein the spacer monomer is a bis (iodo methyl) arene or alkene.  
     
     
         22 . The library according to  claim 18  wherein the spacer monomer is a bis (tosyl methyl) arene or alkene.  
     
     
         23 . The library according to  claim 18  wherein the aromatic monomer contains a sulfhydryl group substituent and the spacer monomer is an α, ω dibromo alkane.  
     
     
         24 . The library according to  claim 18  wherein the aromatic monomer contains a sulfhydryl group substituent and the spacer monomer is an α, ω dichloro alkane.  
     
     
         25 . The library according to  claim 18  wherein the aromatic monomer contains a sulfhydryl group substituent and the spacer monomer is an α, ω diido alkane.  
     
     
         26 . The library according to  claim 18  wherein the aromatic monomer contains a sulfhydryl or hydroxyl substituent has one or more additional substituents on the ring whereby the additional substituents are less electrophillic than the spacer monomers, e.g., these additional substituents may be hydroxyl, sulfhydryl, methoxy, ester, nitro or halogens (such as fluoro, chloro, bromo, iodo groups).  
     
     
         27 . The library according to  claim 18  wherein the ring structures with the hydroxyl group may contain heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen.  
     
     
         28 . The library according to  claim 26  wherein the ring structures with the hydroxyl group may contain heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen.  
     
     
         29 . The library according to  claim 18  wherein the ring structures with the sulfhydryl group may contain heteroatoms selected form the group consisting of nitrogen and oxygen.  
     
     
         30 . The library according to  claim 26  wherein the ring structures with the sulfhydryl group may contain heteroatoms selected form the group consisting of nitrogen and oxygen.  
     
     
         31 . The library according to  claim 19  wherein the structure with the hydroxyl group contains one or more substituents whereby the substituents are non-electrophillic.  
     
     
         32 . The library according to  claim 18  wherein the spacer monomer is linked to the aromatic monomer by a sulfur or oxygen atom.  
     
     
         33 . The library according to  claim 18  wherein the library contains about 75, 75, or 275 members.  
     
     
         34 . A method of making the library according to  claim 4  comprising the steps of: 
 mixing one or more dissolved aromatic monomers to form a mixture,  
 incubating a solution of one or more dibromide spacer monomers with the mixture to form an organic phase, washing and concentrating the organic phase.  
 
     
     
         35 . A method of making the library according to  claim 34  comprising the steps of: 
 dispensing a stoichiometric amount of a dibromide spacer monomer into each well of a microtiter plate or any container having a microtiter plate like well arrangement,  
 dispensing a stoichiometric amount of a single pre-determined aromatic monomer into each well of a vertical column, and  
 dispensing a stoichiometric amount of a single pre-determined aromatic monomer into each well of a horizontal row 2.  
 
     
     
         36 . A compound that binds to a Mahoney poliovirus capsid represented by a structure selected from the group consisting of those structures presented in FIG. 4 a - h.