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Bifunctional small molecules to target the selective degradation of circulating proteins

A protein, bifunctional technology, applied in the direction of organic active ingredients, allergic diseases, non-central analgesics, etc.

Pending Publication Date: 2021-01-15
YALE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] High prevalence of inflammatory diseases in the population imposes a large economic burden on healthcare systems

Method used

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  • Bifunctional small molecules to target the selective degradation of circulating proteins
  • Bifunctional small molecules to target the selective degradation of circulating proteins
  • Bifunctional small molecules to target the selective degradation of circulating proteins

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Embodiment

[0547] Proper protein secretion (section) and turnover are necessary processes to maintain homeostasis. Newly synthesized proteins targeted for secretion are first transported to the endoplasmic reticulum, where they are post-translationally modified with sialic acid-terminal N-linked glycan chains (1). As proteins age, terminal sialic acid residues are removed by circulating endogenous glycosidases (2). This natural protein aging process exposes galactose and N-acetylgalactose (GalNAc) residues, which bind to the asialoglycoprotein receptor (ASGPR) on the surface of hepatocytes (3-5).

[0548] ASGPR is a C-type lectin that removes aged circulating proteins as well as exposed GalNAc residues from circulation by transporting them into lysosomes. Display of multiple galactose or GalNAc residues on the protein surface is essential for high affinity binding - and subsequent endocytosis by - ASGPR (6, 7). Once these proteins are endocytosed, they are released from ASGPR by deplet...

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Abstract

The present invention is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcyRI, FcRN, Transferrin or Macrophage Scavenger receptor. Pharmaceutical compositions based upon these bifunctional small molecules represent an additional aspect of the present invention. These compounds and / or compositions may be used to treat disease states and conditions by removing circulating proteins through degradation in the hepatocytes or macrophages of a patient or subject in need of therapy.Methods of treating disease states and / or conditions in which circulating proteins are associated with the disease state and / or condition are also described herein.

Description

[0001] Related application and funding support [0002] This application claims priority to U.S. provisional applications US62 / 655,055, filed April 9, 2018, and US62 / 788,040, filed January 3, 2019, of the same title as this application, each of which is incorporated by reference in its entirety here. [0003] This invention was made with government support under GM067543 awarded by the National Institutes of Health and W81XWH-13-1-0062 awarded by the U.S. Army Medical Research and Materials Command. The government has certain rights in this invention. [0004] field of invention [0005] The present invention relates to bifunctional small molecules comprising a circulating protein binding moiety (CPBM) linked by a linker group to a cellular receptor binding moiety (collectively referred to as CRBM), preferably to the asialoglycoprotein receptor (asialoglycoprotein receptor) of hepatocytes Acid glycoprotein receptor binding moiety or ASGPRBM) binding moiety. Pharmaceutical co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K47/55A61K47/64A61K31/351C07D309/10A61P35/00A61P29/00A61P37/00
CPCA61K45/06A61P29/00A61P35/00A61P37/00C07H15/26A61K47/549A61K47/55A61K47/64C07D261/20C07D309/04C07D413/02C07D419/02C07H15/04
Inventor D·施皮格尔D·卡亚涅洛M·张
Owner YALE UNIV
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