Dimeric PSD-95 Inhibitors for Ischemic Stroke and Pain
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Solution Overview
Problem
Current PSD-95 inhibitors, such as the Tat-NR2B9c peptide, have low affinity and selectivity for PDZ1-2 domains, limiting their therapeutic effectiveness in treating ischemic stroke, traumatic brain injury, and chronic pain, and are associated with side effects due to non-specific NMDA receptor antagonism.
Innovation Solution
Development of dimeric peptide analogues linked by a PEG linker, with specific sequences and a Cell Penetrating Peptide (CPP) like Tat or Retroinverso-D-Tat, that target PDZ1 and PDZ2 domains of PSD-95, enhancing affinity and stability, and improving blood-brain barrier permeability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If monomeric peptides like Tat-NR2B9c are used to inhibit PSD-95, then they can penetrate the blood-brain barrier, but they have low affinity and selectivity for PDZ1-2 domains
Solution Approach 1:
The patent combines two peptide ligands that bind to PDZ1 and PDZ2 domains respectively, linking them via a PEG linker to create a dimeric structure. This merging of two binding units into one molecule allows simultaneous engagement of both PDZ domains, dramatically increasing affinity (nanomolar range) while maintaining blood-brain barrier penetration capability through the CPP component.
Solution Approach 2:
The invention creates a composite peptide structure integrating three functional components: (1) PDZ1-binding peptide ligand, (2) PDZ2-binding peptide ligand, and (3) cell-penetrating peptide sequence. This composite design achieves multiple objectives - high affinity through dual binding, selectivity through domain-specific recognition, and blood-brain barrier permeability through CPP incorporation.
2Object-affected harmful factors
If NMDA receptor antagonists are used to reduce excitotoxicity, then they can prevent glutamate-mediated ion-flux, but they also prevent physiological important processes and have low tolerance
Solution Approach 1:
The patent extracts and targets only the pathological signaling complex (nNOS-PSD-95-NMDA receptor ternary complex) responsible for excitotoxicity, rather than blocking the entire NMDA receptor. By specifically inhibiting the interaction between PSD-95 and its binding partners PDZ1/PDZ2, the invention disrupts the harmful nitric oxide production pathway while leaving the NMDA receptor's physiological ion-flux and pro-survival signaling intact.
Solution Approach 2:
The dimeric peptide acts as an intermediary that specifically binds to PSD-95's PDZ domains, disrupting the pathological ternary complex formation between nNOS, PSD-95, and NMDA receptor. This intermediary approach selectively interferes with the harmful signaling pathway mediated by PSD-95 scaffolding, while allowing direct NMDA receptor functions to proceed normally.
3Reliability
If current PSD-95 inhibitors are used, then they can inhibit PDZ1-2 domains, but they have low stability in human blood plasma
Solution Approach 1:
The patent incorporates a PEG (polyethylene glycol) linker between the two peptide ligands, which provides enhanced stability in blood plasma. The PEG component protects the peptide bonds from proteolytic degradation by plasma enzymes, extending the half-life and duration of action of the inhibitor while maintaining its ability to bind PDZ1 and PDZ2 domains with high affinity.
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 dimeric peptide analogues demonstrate significantly higher affinity for PDZ1-2 domains, improved stability in human blood plasma, and effective neuroprotection and pain relief with reduced side effects, as shown by reduced infarct volumes and preserved motor function in animal models.
Implementation Method 1
The scaffolding protein PSD-95 is a potential target for treatment of ischemic stroke and traumatic brain injury as well as for chronic pain conditions... dimeric peptide analogues acting as inhibitors of PSD-95-related protein-protein interactions
Implementation Method 2
a third peptide having the function of a Cell Penetrating Peptide (CPP) is linked to the linker
Implementation Method 3
linked by a PEG linker, with specific sequences and a Cell Penetrating Peptide (CPP) like Tat or Retroinverso-D-Tat, that target PDZ1 and PDZ2 domains of PSD-95, enhancing affinity and stability
Data Source
AI summary
The invention provides novel potent inhibitors of the ternary protein complex of nNOS, PSD-95, and the NMDA receptor and pharmaceutical compositions comprising the inhibitors for prophylaxis and/or treatment of excitotoxic-related disease and chronic pain conditions in a subject. The inhibitors are dimeric PSD-95 inhibitors comprising a first peptide or peptide analogue linked to a second peptide or peptide analogue by a linker, wherein the first and the second peptide or peptide analogue comprise at least four amide-bonded residues having a sequence YTXV (SEQ ID NO: 5) or YSXV (SEQ ID NO: 6), wherein a. Y is selected from among E, Q, and A, or an analogue thereof, and b. X is selected from among A, Q, D, N, N-Me-A, N-Me-Q, N-Me-D, and N-Me-N or an analogue thereof, and wherein a Cell Penetrating Peptide (CPP) is linked to the linker or to an amino acid side chain of the first and second peptide or peptide analogue. The linker can be a PEG or NPEG linker.