Peptides for specific inhibition of jag1-notch1 pathway

A signal transduction and signal transmission technology, applied in the direction of peptides, specific peptides, peptide/protein components, etc., can solve problems such as limited strategies and off-target effects

Pending Publication Date: 2021-08-06
THE HONG KONG POLYTECHNIC UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inhibition of furin convertase may have off-target effects
Second, the metalloprotease ADAM10- or ADAM17-dependent cleavage site 2 (S2) for Notch receptors may also be at risk of off-target effects, since ADAMS also involves tumor necrosis factor (TNF) and interleukin-6 Receptor (IL-6R) processing
Jag1 is a promising therapeutic target in Notch signaling [22], however, strategies to target Jag1 interactions remain limited

Method used

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  • Peptides for specific inhibition of jag1-notch1 pathway
  • Peptides for specific inhibition of jag1-notch1 pathway
  • Peptides for specific inhibition of jag1-notch1 pathway

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0063] Materials and methods

[0064] Chemicals and Inhibitors

[0065] All chemicals used in this study were commercially available pure compounds in powder form. N-[N-(3,5-Difluorophenylacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester (DAPT) in the form of white powder was purchased from TCI (Shanghai), Shanghai, China. Topotecan (powder, >98% purity) was purchased from TCI (Shanghai), Shanghai, China. DMEM medium, RPMI-1640 medium, trypsin / ethylenediaminetetraacetic acid and penicillin / streptomycin (P / S) were purchased from Gibco. Fetal bovine serum (FBS) was obtained from HyClone. All other commonly used reagents were purchased from Sigma-Aldrich.

[0066] peptide library

[0067] Oligopeptides derived from the Jag1-Notch1 binary complex of the extracellular domain. Each peptide represents a unique binding site on the extracellular domain. Their sequences range from 5 to 17 amino acids in length, ranging from Jag-1 MNNL to EGF-like 3 and Notch-1 EGF-like 8-12. ...

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Abstract

Aberrant cross talk between Notch ligand (e.g. Jag1) and Notch receptor (e.g. Notch 1) has been implicated in tumorigenesis in the colon. Inhibition of Notch pathway is therefore an attractive approach for treating diseases with upregulated Jagl e.g. colorectal cancer (CRC). Pan-notch inhibitors like gamma-secretase inhibitors (GSIs) have been developed to inhibit Notch and its downstream events. However, severe gastrointestinal toxicity profiles impede the clinical development of GSIs. Provided are novel oligopeptides that specifically inhibit Jag1-Notchl pathway without interfering DLL1 -Notch 1 or DLL4-Notchl, which demonstrate a clear advantage over pan-notch inhibitors.

Description

technical field [0001] The present invention relates to inhibitors of Jag1-Notch1 signaling pathway. Background technique [0002] The Notch signaling pathway is an evolutionarily conserved pathway that contributes to the development of various tissues and organs. The cell-to-cell communication involved in Notch signaling requires the juxtaposition of the signal-sending cell and the signal-receiving cell, with a membrane-tethered Notch ligand on the former binding to a transmembrane Notch receptor on the latter. Mammals have five Notch ligands (Delta-like: DLL1, DLL3, DLL4 and Jagged: Jag1, Jag2) and four Notch receptors (Notch1 to 4). Notch receptors are single-pass transmembrane proteins. The extracellular domain consists of 29 to 36 EGF-like repeats linked to negative regulatory regions (NRRs). Formation of the ligand-receptor binary complex leads to a series of proteolytic events, including the final step in γ-secretase-dependent cleavage to release the Notch intracel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/715C07K7/08C07K9/00A61P35/00A61K38/10
CPCC07K7/08A61P35/00C07K14/705C07K7/06A61K45/06A61K31/4745A61K31/7004A61K38/08A61K38/10A61K2300/00A61K38/00
Inventor 朱雪臻陈友维陈德恒周铭祥
Owner THE HONG KONG POLYTECHNIC UNIV
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