ND2 Peptides Inhibit Src Interaction for Neurological Treatment
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Solution Overview
Problem
Current methods to inhibit the N-methyl D-aspartic acid receptor (NMDAR) complex directly for treating neurological diseases and disorders are hindered by excessive side effects, and there is a need for targeted inhibition of the NADH dehydrogenase subunit 2 (ND2) and Src interaction to modulate NMDA receptor activity without affecting electrical and calcium flux.
Innovation Solution
Development of ND2 peptides and chimeric peptides that specifically target the interaction between ND2 and Src, including peptides with amino acid sequences between 307-321 of ND2, which can be lipidated or linked with internalization peptides to facilitate membrane crossing, thereby inhibiting the ND2-Src interaction and modulating NMDA receptor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If NMDAR complex is inhibited directly to treat neurological diseases, then therapeutic effect is improved, but side effects increase excessively
Solution Approach 1:
The patent segments the NMDAR complex into specific functional components by targeting the ND2-Src interaction specifically, rather than inhibiting the entire NMDAR complex. This selective segmentation allows therapeutic intervention at a specific molecular interface while preserving other NMDAR functions.
Solution Approach 2:
The patent uses peptides as intermediary molecules that specifically bind to the ND2-Src interaction interface. These peptide intermediaries disrupt the pathological ND2-Src binding without directly blocking the NMDAR ion channel, thereby providing therapeutic effect while avoiding the side effects associated with direct NMDAR inhibition.
2Adaptability or versatility
If ND2-Src interaction is inhibited to modulate NMDA receptor activity, then selectivity is improved, but electrical and calcium flux activities may be affected
Solution Approach 1:
The patent extracts and targets specifically the ND2-Src interaction component from the broader NMDAR complex. By focusing intervention on this specific protein-protein interaction rather than the entire receptor complex, the invention achieves high selectivity while preserving the essential electrical and calcium flux activities required for normal neuronal function.
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
These peptides effectively reduce the damaging effects of stroke, pain, and cancer by disrupting the ND2-Src interaction, providing a therapeutic approach with reduced side effects by specifically targeting the NMDAR complex without blocking electrical and calcium flux.
Implementation Method 1
ND2 anchors Src to the N-methyl-d-aspartate (NMDA) receptor complex in postsynaptic densities (PSDs) to regulate NMDA receptor activity
Implementation Method 2
Any of these ND2 peptides can be lipidated, for example, by being linked to a fatty acid. Preferably an ND2 peptide is myristoylated
Data Source
AI summary
The invention is based in part on identifying a core region of ND2 responsible for interacting with Src to within residues 289-321 of ND2 and more particularly residues 307-321 or 310-321 of ND2. Peptides including, overlapping or from within this region can be used to inhibit ND2 interaction with Src Inhibition of this interaction is useful for treatment or prophylaxis of neurological diseases and disorders, pain and cancer.