Protein degradation inducing tag and usage thereof

Abstract

Provided are: a protein degradation inducing tag which is a molecule that has affinity with proteases and does not inhibit degradation of a protein by proteases; a protein degradation inducing molecule that is a conjugate of at least one protein degradation inducing tag and at least one protein binding molecule that binds to a protein; and a usage of those.

1 . A protein-degradation inducing tag, which is a molecule having an affinity with a protease without inhibiting degradation of a protein by the protease. 
     
     
         2 . The protein-degradation inducing tag according to  claim 1 , wherein the protein-degradation inducing tag has a structure where a protease inhibitory activity of a protease inhibitor is inactivated. 
     
     
         3 . The protein-degradation inducing tag according to  claim 1 , wherein the protease is a proteasome. 
     
     
         4 . The protein-degradation inducing tag according to  claim 3 , wherein the protein-degradation inducing tag has a structure where a proteasome inhibitory activity of a proteasome inhibitor is inactivated. 
     
     
         5 . The protein-degradation inducing tag according to  claim 4 , wherein the proteasome inhibiting activity is an inhibitory activity against at least one selected from a caspase-like activity, a trypsin-like activity, and a chymotrypsin-like activity. 
     
     
         6 . A method of screening for a protein-degradation inducing tag, the method including a step of selecting a molecule having an affinity with a protease without inhibiting degradation of a protein by the protease from candidate molecules. 
     
     
         7 . The method of screening for a protein-degradation inducing tag according to  claim 6 , wherein the protease is a proteasome. 
     
     
         8 . A method of manufacturing a protein-degradation inducing tag, the method including a step of modifying a structure of an active site of a protease inhibitor to inactivate a protease inhibitory activity. 
     
     
         9 . The method of manufacturing a protein-degradation inducing tag according to  claim 8 , the method further including a step of selecting, as the protease inhibitor, a molecule having an affinity with a protease and inhibiting degradation of a protein by the protease from candidate molecules. 
     
     
         10 . A library of protein-degradation inducing tags, comprising two or more types of protein-degradation inducing tags, each of the two or more types of protein-degradation inducing tags being the protein-degradation inducing tag according to any one of  claims 1  to  5 . 
     
     
         11 . A protein-degradation inducing molecule, which is a conjugate of at least one protein-degradation inducing tag and at least one protein binding molecule capable of binding to a protein, the at least one protein-degradation inducing tag being the protein-degradation inducing tag according to any one of  claims 1  to  5 . 
     
     
         12 . A library of protein-degradation inducing molecules, comprising two or more types of protein-degradation inducing molecules, each of the two or more types of protein-degradation inducing molecules being the protein-degradation inducing molecule according to  claim 11 . 
     
     
         13 . A pharmaceutical composition, comprising the protein-degradation inducing tag according to any one of  claims 1  to  5  or the protein-degradation inducing molecule according to  claim 11 . 
     
     
         14 . A method of degrading a target protein, the method comprising a step of inducing degradation of the target protein using the protein-degradation inducing tag according to any one of  claims 1  to  5  or the protein-degradation inducing molecule according to  claim 11 . 
     
     
         15 . A method of performing functional analysis on a target protein, the method comprising a step of inducing degradation of the target protein using the protein-degradation inducing tag according to any one of  claims 1  to  5  or the protein-degradation inducing molecule according to  claim 11 . 
     
     
         16 . A method of identifying a target protein, the method comprising a step of inducing degradation of the target protein using the protein-degradation inducing tag according to any one of  claims 1  to  5  or the protein-degradation inducing molecule according to  claim 11 , and
 a step of identifying a protein subjected to degradation induced by the protein-degradation inducing tag or the protein-degradation inducing molecule. 
 
     
     
         17 . A method of identifying a pathway molecule through a target protein, the method comprising a step of inducing degradation of the target protein using the protein-degradation inducing tag according to any one of  claims 1  to  5  or the protein-degradation inducing molecule according to  claim 11 , and
 a step of identifying a protein showing an altered activity or expression, the protein being different from the target protein. 
 
     
     
         18 . A method of screening for a protein-degradation inducing tag or a protein-degradation inducing molecule, the method comprising a step of introducing the protein-degradation inducing tag according to any one of  claims 1  to  5 , the library of protein-degradation inducing tags according to  claim 10 , the protein-degradation inducing molecule according to  claim 11 , or the library of protein-degradation inducing molecules according to  claim 12  into a system including a target protein, and selecting a protein-degradation inducing tag or protein-degradation inducing molecule which has induced degradation of the target protein. 
     
     
         19 . The method of screening for a protein-degradation inducing tag or a protein-degradation inducing molecule according to  claim 18 , wherein the target protein is a disease causative agent, and the protein-degradation inducing tag or the protein-degradation inducing molecule which has induced degradation of the target protein is selected as a candidate ingredient for preventing or treating a disease. 
     
     
         20 . A method of screening for a candidate ingredient for preventing or treating a disease, the method comprising a step of introducing the protein-degradation inducing tag according to any one of  claims 1  to  5 , the library of protein-degradation inducing tags according to  claim 10 , the protein-degradation inducing molecule according to  claim 11 , or the library of protein-degradation inducing molecules according to  claim 12  into a disease model system, and selecting a protein-degradation inducing tag or a protein-degradation inducing molecule which improves a condition of the disease. 
     
     
         21 . A method of screening for a candidate ingredient for preventing or treating a disease, the method comprising a step of introducing the protein-degradation inducing tag according to any one of  claims 1  to  5 , the library of protein-degradation inducing tags according to  claim 10 , the protein-degradation inducing molecule according to  claim 11 , or the library of protein-degradation inducing molecules according to  claim 12  into a disease model system, and extracting a protein-degradation inducing tag or a protein-degradation inducing molecule which aggravates a condition of the disease, and selecting a protein subjected to degradation induced by the extracted protein-degradation inducing tag or the extracted protein-degradation inducing molecule. 
     
     
         22 . A method of specifying a disease-related protein, the method comprising a step of introducing the protein-degradation inducing tag according to any one of  claims 1  to  5 , the library of protein-degradation inducing tags according to  claim 10 , the protein-degradation inducing molecule according to  claim 11 , or the library of protein-degradation inducing molecules according to  claim 12  into a disease model system, and extracting a protein-degradation inducing tag or a protein-degradation inducing molecule which has altered a condition of a disease, and selecting a protein subjected to degradation induced by the extracted protein-degradation inducing tag or the extracted protein-degradation inducing molecule.