Protein degradation inducing tag and usage thereof

Patent metadata

Field	Value
Publication number	US-10976306-B2
Application number	US-201615736089-A
Country	US
Kind code	B2
Filing date	Jun 15, 2016
Priority date	Jun 19, 2015
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

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.

First claim

The invention claimed is:

1. 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 target protein, the at least one protein-degradation inducing tag being a molecule having a molecular weight of 5000 or less and having an affinity with a 26S proteasome without inhibiting degradation of the target protein by the 26S proteasome,
the protein-degradation inducing molecule leading the target protein bound to the protein binding molecule to degradation by the 26S proteasome.

2. A library of protein-degradation inducing molecules, comprising two or more protein-degradation inducing molecules according to claim 1 .

3. A pharmaceutical composition, comprising a protein-degradation inducing molecule according to claim 1 and a pharmaceutically acceptable carrier.

4. A method of degrading a target protein, the method comprising a step of contacting the target protein with a protein-degradation inducing molecule according to claim 1 to result in degradation of the target protein.

5. 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 target protein, the at least one protein-degradation inducing tag being a molecule having an affinity with a 26S proteasome without inhibiting degradation of the target protein by the 26S proteasome,
the protein-degradation inducing molecule leading the target protein bound to the protein binding molecule to degradation by the 26S proteasome.

6. A culture medium for culturing cells, a tissue, or an organ comprising the protein-degradation inducing molecule according to claim 5 .

7. A method for inducing protein degradation of a eukaryote or prokaryote having a protease in a living body, comprising orally or parenterally administering the protein-degradation inducing molecule according to claim 5 to said living body.

8. 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 target protein, the at least one protein-degradation inducing tag being a molecule having an affinity with a 26S proteasome without inhibiting degradation of the target protein by the 26S proteasome,
the protein-degradation inducing molecule leading the target protein bound to the protein binding molecule to degradation by the 26S proteasome,
wherein the protein-degradation inducing tag has a structure represented by the formula (I), or a structure where a proteasome inhibitory activity of a proteasome inhibitor is inactivated, or a structure of a proteasome activating agent:

wherein R 1 and R 2 each independently represent a hydrocarbon group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, an aryloxy group having 6 to 20 carbon atoms, a hydroxy group, a carboxy group, an amino group, or a halogeno group.

9. A library of protein-degradation inducing molecules, comprising two or more protein-degradation inducing molecules, each of the two or more protein-degradation inducing molecules being the protein-degradation inducing molecule according to claim 8 .

10. A pharmaceutical composition, comprising the protein-degradation inducing molecule according to claim 8 and a pharmaceutically acceptable carrier.

11. A method of degrading a target protein, comprising contacting the target protein with the protein-degradation inducing molecule according to claim 8 to result in degradation of the target protein.

Assignees

• Univ Tokyo Science Found

Inventors

• Miyamoto Etsuko
• Ozawa Masaaki

Classifications

• C12N9/6427 Primary

  Chymotrypsins (3.4.21.1; 3.4.21.2); Trypsin (3.4.21.4) · CPC title

• C07D239/49

  with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim · CPC title

• C12Q1/02

  involving viable microorganisms · CPC title

• C07K19/00

  Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes} · CPC title

• C07K2319/95

  containing a motif/fusion for degradation (ubiquitin fusions, PEST sequence) · CPC title