Compounds displayed on replicable genetic packages and methods of using same

Abstract

Replicable genetic packages and collections thereof that display various compounds are provided. In some instances, the replicable genetic packages include nucleic acid tags that serve to record a characteristic of the compound or compounds that are attached to the replicable genetic package. The invention further provides a number of different methods for using the replicable genetic packages to screen a library of compounds for a desired biological activity.

1 - 146 . (canceled) 
     
     
         147 . A method of screening a library of compounds, comprising:
 (a) providing a plurality of replicable genetic packages, each of the replicable genetic packages displaying a compound other than a polypeptide expressed by the replicable genetic packages, different replicable genetic packages displaying different compounds and harboring different heterologous nucleic acid tags, wherein:   each of the heterologous nucleic acid tags is a nucleic acid segment other than a segment that encodes for a polypeptide displayed on the replicable genetic packages; and   each of the compounds is associated with a specific heterologous nucleic acid tag;   (b) assaying the plurality of replicable genetic packages to identify at least one replicable genetic package displaying at least one compound with a desired property; and   (c) decoding the heterologous nucleic acid tag of the at least one replicable genetic package to identify a characteristic of the at least one compound with the desired property.   
     
     
         148 . The method of  claim 147 , further comprising generating a correspondence regime indicating which compound is attached to which replicable genetic package. 
     
     
         149 . The method of  claim 148 , wherein the correspondence regime is a correspondence regime between the compounds and the heterologous nucleic acid tags harbored by the replicable genetic packages, and the characteristic of the at least one compound is determined by matching the sequence of the heterologous nucleic acid tag of the at least one replicable genetic package and a sequence of the heterologous nucleic acid tag in the correspondence regime. 
     
     
         150 . The method of  claim 147 , wherein each compound is contacted with one or more replicable genetic packages that each harbor the same heterologous nucleic acid tag, whereby each of the one or more replicable genetic packages contacted bears the same compound; wherein:
 replicable genetic packages harboring the same heterologous nucleic acid tags display the same compound; and   replicable genetic packages harboring different heterologous nucleic acid tags display different compounds.   
     
     
         151 . The method of  claim 147 , wherein
 (a) the library of compounds to be screened are separated into a plurality of pools, each pool comprising a plurality of compounds from the library; contacting each pool of compounds with one or more replicable genetic packages that harbor the same heterologous nucleic acid tag, whereby each of the one or more replicable genetic packages that harbors the same heterologous nucleic acid tag displays a plurality of different compounds; and combining the one or more replicable genetic packages from the plurality of pools to provide the plurality of replicable genetic packages; and   (b) assaying comprises
 (i) assaying the plurality of replicable genetic packages to identify an initial replicable genetic packages displaying a compound wherein at least one of the plurality of compounds has the desired property; and 
 (ii) repeating the assay with a set of replicable genetic packages, wherein each member of the set displays one of the compounds borne by the initial replicable genetic packages to identify the at least one replicable genetic package. 
   
     
     
         152 . The method of  claim 147 , wherein the decoding step is performed by sequencing the heterologous nucleic acid tag of the at least one replicable genetic package. 
     
     
         153 . The method of  claim 147 , wherein the decoding step comprises:
 (a) generating a nucleic acid probe from the at least one replicable genetic package, the nucleic acid probe comprising or being complementary to the heterologous nucleic acid tag of the at least one replicable genetic package; and   (b) contacting the probe to the heterologous nucleic acid tag from the plurality of replicable genetic packages to identify the replicable genetic packages displaying the at least one compound.   
     
     
         154 . The method of  claim 153 , further comprising determining the identity of the at least one compound from a correspondence regime between different replicable genetic packages and different compounds. 
     
     
         155 . The method of  claim 153 , wherein the replicable genetic packages are arranged in an array for the contacting step. 
     
     
         156 . The method of  claim 147 , wherein the desired property is selected from the group consisting of the capacity to bind to a receptor, the capacity to be transported into or through a cell, the capacity to be a substrate or inhibitor for an enzyme, the capacity to kill bacteria fungi or other microorganisms, and the capacity to agonize or antagonize a receptor. 
     
     
         157 . The method of  claim 156 , wherein the desired property is the capacity to bind to a receptor and the assaying step comprises contacting the plurality of replicable genetic packages displaying different compounds with the receptor and identifying at least one replicable genetic package displaying a compound that binds to the receptor. 
     
     
         158 . The method of  claim 156 , wherein the desired property is the capacity to be transported into or through a cell and the assaying step comprises contacting the plurality of replicable genetic packages displaying different compounds with the cell and identifying at least one replicable genetic package displaying a compound that is transported into or through the cell. 
     
     
         159 . The method of  claim 156 , wherein the desired property is the capacity to be a substrate or inhibitor of an enzyme and the assaying step comprises contacting the plurality of replicable genetic packages with the enzyme and identifying at least one replicable genetic package displaying a compound that is a substrate or an inhibitor of the enzyme. 
     
     
         160 . A method of screening a library of compounds, comprising:
 (a) providing a plurality of replicable genetic packages each of the replicable genetic packages displaying a compound other than a polypeptide expressed by the replicable genetic packages, and harboring a heterologous nucleic acid tag, wherein:   the heterologous nucleic acid tag is a nucleic acid segment other than a segment that encodes for a polypeptide displayed on the replicable genetic packages; and   each compound is associated with a specific heterologous nucleic acid tag;   (b) assaying the plurality of replicable genetic packages to identify at least one replicable genetic package displaying at least one compound with a desired property; and   (c) decoding the heterologous nucleic acid tag of the at least one replicable genetic package to identify a characteristic of the at least one compound with the desired property.   
     
     
         161 . The method of  claim 160 , wherein the plurality of replicable genetic packages are combined into a pool and the pool is contacted with a compound of the library, the harboring different heterologous nucleic acid tags, whereby replicable genetic packages harboring different heterologous nucleic acid tags bear the same compound. 
     
     
         162 . The method of  claim 160 , wherein the library of compounds to be screened are combined into a pool and the plurality of replicable genetic packages harboring different heterologous nucleic acid tags are combined into a pool, and the pool of replicable genetic packages is contacted with the pool of compounds, whereby replicable genetic packages harboring different tags bear the same plurality of compounds. 
     
     
         163 . A method of screening a library of compounds, comprising:
 (a) for each compound to be screened, contacting each compound with a replicable genetic package to form a plurality of replicable genetic packages displaying different compounds and harboring different heterologous nucleic acid tags; wherein:   each of the heterologous nucleic acid tags is a nucleic acid segment other than a segment that encodes for a polypeptide displayed on the replicable genetic packages; and   (b) assaying the replicable genetic packages displaying different compounds to identify at least one replicable genetic package displaying at least one compound with a desired property.   
     
     
         164 . The method of  claim 163 , wherein the method further comprises decoding the heterologous nucleic acid tag of the at least one replicable genetic package to identify a characteristic of the at least one compound with the desired property. 
     
     
         165 . The method of  claim 147 , wherein each of the replicable genetic packages is of the same type and is selected from any one of cells, spores, virus, bacterium, and bacteriophage. 
     
     
         166 . The method of  claim 160 , wherein each of the replicable genetic packages is of the same type and is selected from any one of cells, spores, virus, bacterium, and bacteriophage. 
     
     
         167 . The method of  claim 163 , wherein each of the replicable genetic packages is of the same type and is selected from any one of cells, spores, virus, bacterium, and bacteriophage.