Neuregulin Peptides ErbB2 Receptor Binding Heart Failure
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Solution Overview
Problem
Current treatments for heart failure, such as ACE inhibitors and mechanical devices, have limitations in effectiveness and invasiveness, and there is a need for more effective therapies to prevent or treat cardiac hypertrophy and heart failure.
Innovation Solution
Development of neuregulin peptides with enhanced affinity for the ErbB2 receptor, specifically comprising an EGF domain of the human neuregulin β2 isoform, which can be administered to induce phosphorylation of ErbB receptors and activate the ERK signaling pathway, thereby treating cardiac diseases and disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current drug therapy (ACE inhibitors) is used to treat heart failure, then blood pressure is reduced and heart workload is reduced, but the mortality reduction is only 3%-4% and there are potential side effects
Solution Approach 1:
The patent modifies the amino acid sequence parameters of neuregulin peptides to enhance their affinity for ErbB2 receptors. Specifically, the invention uses variants with substitutions at positions 44, 47, 50, and 53 (e.g., NRG44, NRG47, NRG50, NRG53 variants) to optimize receptor binding characteristics, thereby improving therapeutic efficacy while potentially reducing required dosage and associated side effects
Solution Approach 2:
The patent creates composite therapeutic approaches by combining neuregulin peptides with enhanced ErbB2 affinity with existing heart failure treatments. The invention describes using these peptides in combination with ACE inhibitors, beta-blockers, and other conventional therapies to achieve synergistic effects that improve mortality reduction beyond what single therapies can achieve
2Ease of operation
If combination therapy with digitalis and diuretics is administered, then some symptoms are improved, but survival shows no difference compared to placebo
Solution Approach 1:
The patent segments the therapeutic approach by identifying and targeting the specific ErbB2 receptor pathway separately from other conventional heart failure treatment pathways. The invention focuses on activating the neuregulin-ErbB2 signaling cascade as a distinct mechanism that addresses survival and mortality outcomes, rather than relying solely on symptom management through combination therapies
3Reliability
If heart transplantation or mechanical devices are used, then heart failure is treated, but the procedures are more expensive and invasive
Solution Approach 1:
The patent replaces mechanical intervention (transplantation, mechanical devices) with a biochemical therapeutic approach. The invention uses neuregulin peptides that activate cellular signaling pathways to improve cardiac function, thereby substituting invasive mechanical systems with a molecular-level biochemical intervention that is less invasive and potentially more scalable
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The neuregulin peptides demonstrate improved affinity for ErbB receptors and possess biological activities that enhance cardiac function, potentially delaying or preventing heart failure and cardiac hypertrophy, offering a promising therapeutic approach with potential for clinical use.
Implementation Method 1
NRG binds to the extracellular domain of ErbB3 or ErbB4, it induces a conformational change that leads to heterodimer formation between ErbB3, ErbB4 and ErbB2 or homodimer formation between ErbB4 itself, which results in phosphorylation of the receptors' C-terminal domain inside the cell membrane
Implementation Method 2
The phosphorylated intracellular domain then binds additional signal proteins inside the cell, activating the corresponding downstream AKT or ERK signaling pathway
Data Source
Figure 1
AI summary
The present invention relates to a neuregulin peptide consisting essentially of or consisting of the amino acid sequence selected from the group consisting of SEQ ID NO:9, SEQ ID NO:3, SEQ ID NO:7 and SEQ ID NO:5 as specified herein. The present invention further relates to a pharmaceutical composition comprising the said neuregulin peptide and a pharmaceutically acceptable carrier, excipient, or diluent. The present invention also relates to the said neuregulin peptide for use in a method of treating heart failure in a subject.