Synergistic Polyamine and Histidine Dipeptide Composition for TFEB Activation
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Solution Overview
Problem
Current therapies for enhancing TFEB-mediated intracellular clearance are limited by the need for long-term use of mTOR inhibitors, which have side effects, and the poor blood-brain barrier permeability of disaccharides like trehalose and sucrose.
Innovation Solution
A synergistic composition comprising N-(3-Aminopropyl)-1,4-butanediamine and N-α-Acetyl-N-β-alanyl-L-histidine, in specific weight ratios, along with pharmaceutically acceptable excipients, which work synergistically to enhance TFEB gene expression and promote intracellular clearance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mTOR inhibitors are used to enhance TFEB-mediated intracellular clearance, then autophagy and lysosomal biogenesis are improved, but long-term use causes side effects
Solution Approach 1:
The patent changes the chemical parameters by using polyamines (spermidine, spermine) and disaccharides (trehalose, sucrose) with specific molecular structures and properties that activate TFEB through a different mechanism than mTOR inhibition, thereby achieving autophagy enhancement without the harmful side effects of long-term mTOR inhibitor use
Solution Approach 2:
The patent introduces polyamines and disaccharides as intermediary substances that mediate TFEB activation directly, bypassing the mTOR pathway. These intermediaries bind to or modify TFEB to promote its nuclear translocation and transcriptional activity, providing a safer alternative to mTOR inhibitors
2Reliability
If disaccharides like trehalose and sucrose are used to enhance TFEB-mediated clearance, then intracellular clearance is improved, but blood-brain barrier permeability is poor
Solution Approach 1:
The patent creates a composite formulation containing polyamines, disaccharides, and amino acids in specific ratios. This composite composition leverages the synergistic effects of multiple components, where polyamines enhance TFEB activation and amino acids may facilitate blood-brain barrier penetration, collectively overcoming the permeability limitation of disaccharides alone
Solution Approach 2:
The patent employs polyamines that serve multiple functions: they activate TFEB directly, enhance autophagy, and potentially improve blood-brain barrier permeability. This multi-functional approach addresses both the intracellular clearance benefit and the delivery challenge simultaneously
Data Source
AI summary
Compositions for enhancing TFEB-mediated intracellular clearance are herein. Particularly, a complex comprising synergistic combination of polyamine and histidine-containing dipeptide present in a specific weight ratio along with pharmaceutically acceptable excipients is provided herein. More particularly, the composition comprises a synergistic blend of N-(3-Aminopropyl)-1,4-butanediamine and N-α-Acetyl-N-β-alanyl-L-histidine and salts thereof along with pharmaceutically acceptable excipients. Furthermore, the present synergistic composition is useful for improving or inducing autophagy, lysosomal biogenesis, mitophagy and lipophagy.