Fatty Acid-D-Amino Acid Conjugates for TCA Cycle Replenishment
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for propionic acidemia, methylmalonic acidurias, glutaric acidemias, and fatty acid oxidation disorders are inadequate in replenishing deficient TCA cycle intermediates, leading to mitochondrial dysfunction and reduced ATP production.
Innovation Solution
Administration of fatty acid-D-amino acid peptide conjugates, such as adipic acid-D-Ala-D-His or methylmalonic acid-D-His, which enter the Krebs cycle as intermediates, replenishing succinyl-CoA and other anaplerotic compounds to normalize TCA cycle intermediates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for propionic acidemia and methylmalonic acidurias, then the disease symptoms are managed, but TCA cycle intermediates remain deficient leading to mitochondrial dysfunction
Solution Approach 1:
The patent uses fatty acid-D-amino acid peptide conjugates as intermediary compounds that serve dual functions: the fatty acid portion provides anaplerotic substrates for TCA cycle intermediate synthesis, while the D-amino acid peptide portion enhances absorption and delivery to mitochondrial sites. This intermediary approach bridges the gap between conventional treatment and the needed replenishment of TCA cycle intermediates.
Solution Approach 2:
The invention combines fatty acid moieties with D-amino acid peptides to create composite molecular structures. These conjugates integrate the metabolic precursor function of fatty acids with the enhanced bioavailability properties of D-amino acid peptides, achieving simultaneous delivery of anaplerotic substrates and improved cellular uptake for replenishing TCA cycle intermediates.
2Reliability
If conventional treatments are used, then disease management is maintained, but mitochondrial ATP production remains reduced
Solution Approach 1:
The patent employs D-amino acid peptides in the conjugates to pre-facilitate absorption and transport processes before the fatty acid anaplerotic substrates reach their mitochondrial metabolic targets. This preliminary action by the D-amino acid component ensures efficient delivery and uptake, enabling subsequent restoration of TCA cycle function and ATP production.
3Quantity of substance
If simple fatty acid supplements are administered, then anaplerotic substrates are provided, but absorption and delivery to mitochondria are insufficient
Solution Approach 1:
The patent creates composite fatty acid-D-amino acid peptide conjugates where the D-amino acid peptide component provides enhanced absorption characteristics. This composite structure combines the anaplerotic substrate function of fatty acids with the improved bioavailability and mitochondrial targeting properties of D-amino acid peptides, resolving the contradiction between substrate quantity and delivery efficiency.
Data Source
AI summary
Provided herein is a method of providing an anaplerotic compound to a patient in need therefor. The method may be used to treat the patient for a propionic acidemia. a methymalonic aciduria, or a fatty acid oxidation disorder. Also provided herein are compounds useful in those methods. the compounds comprising an adipic acid or methylmalonic acid moiety linked to from one to three amino acids, e.g. D-amino acids, such as D-Ser, D-His, D-Lys, D-Leu, and/or D-Ala.