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Neuregulin variants and methods of screening and using thereof

a technology of neutropenia and variants, applied in the field of neutropenia variants, can solve the problems of nrg-1 significantly prolonging the survival of heart failure animals, affecting the survival of animals with cardiac disease, and affecting the survival of animals with nrg-1. , to achieve the effect of enhancing the binding affinity of erbb3, preventing, treating or delaying developmen

Inactive Publication Date: 2007-09-13
ZENSUN (SHANGHAI) SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a polypeptide variant of neuregulin-1β that has an enhanced binding affinity to ErbB3 compared to the polypeptide of SEQ ID NO:1. This polypeptide variant can be used in the prevention, treatment, or delay of diseases that are associated with the activation of ErbB2 / ErbB3 receptors, such as schizophrenia. The polypeptide variant has a different amino acid sequence at residues 25, 35, or 46, or a combination of these residues. The polypeptide variant can also have a decreased or similar binding affinity to ErbB4 compared to the polypeptide of SEQ ID NO:1. The invention also provides a polynucleotide encoding the polypeptide variant and a pharmaceutical composition comprising the polypeptide variant.

Problems solved by technology

Targeted disruption of the NRG-1β, or ErbB2 or ErbB4 led to embryonic lethality due to cardiac development defects.
More importantly, NRG-1β significantly prolongs survival of heart failure animals.

Method used

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  • Neuregulin variants and methods of screening and using thereof
  • Neuregulin variants and methods of screening and using thereof
  • Neuregulin variants and methods of screening and using thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

for NRG-1β Variants that Selectively Activate a ErbB Receptor

Methods

1. Construction of 3D Models of the Proteins

[0118] The x-ray crystal structure of the human EGF and receptor extracellular domains (PDB entry 1IVO) and NMR structure of Neuregulin-alpha (NRG-α) epidermal growth factor (EGF)-like domain (PDB entry 1HAF) were obtained from the Protein Data Bank. The amino acid sequences of ErbB3 (ERB3_HUMAN), ErbB4 (ERB4_HUMAN); and NRG-1β (NRG1_HUMAN) were obtained from the Swiss_Prot / TrEMBL database.

[0119] All models were generated using the Homology module of the Insight II software (Accelrys Corporate, San Diego, Calif.). The NMR coordinates of Neuregulin-α were used to model the initial structure of Neuregulin-1β (NRG-1β177-229). The pairwise sequence alignments between the target sequences of ErbB3 and ErbB4 and the template EGFR sequence were performed against each of the homology sequences, respectively. The position of the disulphide bonds between the cysteine residues w...

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Abstract

The present invention provides polypeptide variants of neuregulin-1β (NRG-1β) that have enhanced or decreased binding affinity to ErbB3 and / or ErbB4. The invention also provides methods of screening and producing polypeptide variants of NRG-1β and methods of using polypeptide variants of NRG-1β for treating diseases.

Description

FIELD OF THE INVENTION [0001] This invention relates generally to neuregulin variants that selectively activate ErbB receptors. The invention provides neuregulin variants and methods for screening and using such variants. BACKGROUND OF THE INVENTION [0002] The epidermal growth factor receptor family, which comprises four members EGFR, ErbB2, ErbB3 and ErbB4, has been demonstrated to play an important role in multiple cellular functions, including cell growth, differentiation and survival. They are protein tyrosine kinase receptors, consisting of an extracellular ligand-binding domain, transmembrane domain and cytoplasmic tyrosine kinase domain. Multiple receptor ligands have been identified which mediate receptor homo- or hetero-dimerization upon binding. The specific receptor association results in different patterns of phosphorylation, complex signaling cascades and multiple biological functions, including cellular proliferation, prevention of apoptosis and promotion of tumor cell...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17G06F19/00C07K14/47G16B15/30G16B20/30G16B20/50
CPCA61K38/00C07K14/4756G01N2800/32G01N2333/4756G01N2500/02G01N33/6872G16B15/00G16B20/00A61P25/00A61P25/18A61P31/12A61P9/00A61P9/10Y02A90/10G16B20/30G16B20/50G16B15/30
Inventor ZHOU, MINGDONG
Owner ZENSUN (SHANGHAI) SCI & TECH CO LTD
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