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Polypeptide PROTAC molecule as well as preparation method and application thereof

A molecular and reaction unit technology, applied in the field of polypeptide PROTAC molecules and their preparation, can solve the problems of not being able to bring the target protein and E3 ligase closer, and limiting the clinical transformation of PROTAC molecules.

Pending Publication Date: 2022-05-31
THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, PROTAC molecules are still facing many potential problems and challenges: (1) Small molecule PROTACs have a hook effect (HOOK effect), that is, they tend to bind to a single E3 ligase or target protein at high concentrations, rather than to bind two at the same time. protein, so that it cannot play the function of bringing the target protein closer to the E3 ligase
This dose-independent protein degradation greatly limits the clinical translation of PROTAC molecules
(2) The distribution of PROTAC molecules in non-targeted normal tissues and organs triggered by potential off-target effects, resulting in toxicity, which limits the clinical transformation of PROTAC molecules

Method used

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  • Polypeptide PROTAC molecule as well as preparation method and application thereof
  • Polypeptide PROTAC molecule as well as preparation method and application thereof
  • Polypeptide PROTAC molecule as well as preparation method and application thereof

Examples

Experimental program
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Embodiment 1

[0151] This embodiment provides a polypeptide nanoprotein ubiquitination degradation agent, which can activate and catalyze the click reaction process under the reduction of GSH in tumor cells, and trigger the assembly process at the same time. A nanofibrous polypeptide nanoprotein ubiquitination degradation agent is formed, and the formation process schematic diagram of the nanofibrous polypeptide nanoprotein ubiquitination degradation agent is as follows figure 1 shown.

[0152] The module molecule A of the polypeptide nanoprotein ubiquitination degradation agent targets and recognizes E3 ligase VHL Ligand 1, and the module molecule B targets and recognizes AR; the module molecule A is GHK (Cu 2+ )K(N 3 )-E-(VHL-1)GNNQQNY, the structure of the module molecule A is as figure 2 Shown; The module molecule B is GHK (Cu 2+ ) Pra-K-(Enza)GNNQQNY, the structure of the module molecule B is as image 3 shown.

[0153] In module molecule A and module molecule B, in GHK, G (glyci...

Embodiment 2

[0168] This embodiment provides a polypeptide nanoprotein ubiquitination degradation agent, the module molecule A of the polypeptide nanoprotein ubiquitination degradation agent is consistent with the module molecule A in Example 1, and the module molecule B targets and recognizes EGFR; Module molecule A is GHK(Cu 2+ )K(N 3 )-E-(VHL-1)GNNQQNY; the module molecule B is GHK(Cu 2+ ) Pra-K-(Gefi)GNNQQNY, the structure of the module molecule B is as Figure 4 Shown; In the module molecule B, Gefi represents a gefitinib derivative. The preparation method of the polypeptide nanoprotein ubiquitination degradation agent refers to the preparation method of Example 1.

Embodiment 3

[0170] This embodiment provides a polypeptide nanoprotein ubiquitination degradation agent, the module molecule A of the polypeptide nanoprotein ubiquitination degradation agent targets and recognizes the E3 ligase CRBN, and the module molecule B is consistent with the module molecule B in Example 1 ; The module molecule A is GHK (Cu 2+ )K(N 3 )-E-(CRBN)GNNQQNY, the structure of the module molecule A is as Figure 5 shown.

[0171] In module molecule A, CRBN represents a targeting molecule targeting E3 ligase CRBN. The preparation method of the polypeptide nanoprotein ubiquitination degradation agent refers to the preparation method of Example 1.

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Abstract

The invention provides a polypeptide PROTAC molecule and a preparation method and application thereof, the polypeptide nano protein ubiquitination degradation agent is a proteolysis targeting chimera based on a ubiquitination-proteasome system, and the polypeptide nano protein ubiquitination degradation agent comprises a module molecule, the module molecule comprises a module molecule A and a module molecule B, the module molecule A comprises a coupling group A, a self-assembly group and an E3 ligase recognition group, the module molecule B comprises a coupling group B, a self-assembly group and a targeted binding group, and the coupling group A and the coupling group B are used for connecting the module molecule A and the module molecule B. The polypeptide nano protein ubiquitination degradation agent can realize dose-dependent degradation, can be specifically triggered in a tumor area, remarkably reduces off-target toxicity, and is a protein ubiquitination degradation agent with selectivity and specificity.

Description

technical field [0001] The invention belongs to the field of biotechnology, and in particular relates to a polypeptide PROTAC molecule and its preparation method and application. Background technique [0002] The occurrence and development of most diseases are related to the abnormal expression or aggregation of proteins. For the pathological mechanism of such diseases, the traditional drug development idea is to develop small molecule inhibitors or protein inhibitors, by occupying and blocking the target protein. The active site of action inhibits the functional activity of the protein. In the traditional drug research and development thinking, the target protein is required to have active pockets and binding sites. At the same time, this mode driven by occupancy needs to maintain a high drug concentration for a period of time to exert a good therapeutic effect, but a higher Drug concentration can easily cause off-target effects and adverse reactions. In addition, small m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/02C07K7/08C07K1/06C07K1/04A61K38/10A61P35/00
CPCC07K7/02C07K7/08A61P35/00A61K38/00Y02P20/55
Inventor 王浩安红维张薿元侯大勇
Owner THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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