Alpha-1-Antitrypsin Polymerization Inhibition via Cryptic Site Binding
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Solution Overview
Problem
Current therapies for alpha-1-antitrypsin deficiency, particularly for mutant Z-antitrypsin, are limited in addressing liver disease and lung tissue damage due to the accumulation of polymerized Z-antitrypsin, with existing treatments focusing on protein replacement and lacking effective methods to inhibit polymerization.
Innovation Solution
Development of small molecule compounds that bind to alpha-1-antitrypsin, specifically targeting the cryptic binding site between β-sheet-A and β-sheet-B, inhibiting polymerization and providing therapeutic benefits by forming hydrogen bonds with specific amino acids, thereby preventing the formation of harmful protein polymers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If protein replacement therapy with M-AT is used, then lung pathology including emphysema is treated effectively, but liver disease caused by accumulation of polymerized Z-AT has no effect
Solution Approach 1:
The invention segments the approach into two distinct mechanisms: (1) protein replacement therapy (M-AT) that addresses lung pathology by providing functional protease inhibitor, and (2) polymerization inhibition compounds that specifically target and prevent Z-AT polymer accumulation in the liver. This segmentation allows each therapy to be optimized for its specific indication without compromising the other.
Solution Approach 2:
The patent introduces small molecule compounds as intermediary agents that bind to Z-AT and prevent polymerization. These compounds act as mediators between the mutated protein and the cellular environment, stabilizing Z-AT in its monomeric form and preventing its accumulation in the ER, thereby addressing liver disease without interfering with the protein replacement therapy for lung conditions.
2Reliability
If liver transplantation is performed for Z-AT afflicted liver disease, then fibrosis, cirrhosis and hepatocellular carcinoma are treated, but it is the only treatment option available and carries significant risk
Solution Approach 1:
The invention applies preliminary action by using polymerization inhibition compounds to prevent Z-AT polymer accumulation before it progresses to fibrosis, cirrhosis, or hepatocellular carcinoma. By stabilizing Z-AT in its monomeric form early in the disease process, the compounds can prevent the need for liver transplantation, thereby avoiding the complexity and risks associated with the procedure.
3Ease of manufacture
If Z-AT polymer accumulation is allowed to occur, then protein replacement therapy can be simplified, but harmful polymers are formed that cause tissue damage and inflammation
Solution Approach 1:
The invention applies preliminary anti-action by using compounds that specifically target and prevent Z-AT polymerization before harmful polymers can form. These compounds bind to Z-AT and stabilize it in its monomeric form, preemptively preventing the formation of polymer aggregates that would otherwise cause tissue damage and inflammation in the liver and other organs.
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 compounds effectively inhibit Z-antitrypsin polymerization, offering a potential treatment for diseases associated with alpha-1-antitrypsin deficiency, including liver and lung diseases, by stabilizing the protein structure and reducing tissue damage.
Implementation Method 1
the binding site may be located between β-sheet-A and β-sheet-B of said α1-antitrypsin, wherein: said β-sheet-A comprises the amino acids corresponding to residues 140-144, 111-121, 181-191, 330-340 and 292-299 of SEQ ID NO: 1; and said β-sheet-B comprises the amino acids corresponding to residues 228-231, 236-244, 248-256, 369-376, 381-389, and 49-53 of SEQ ID NO: 1
Data Source
AI summary
The present invention relates to compounds, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, for example as modulators of alpha 1 antitrypsin and treating diseases associated with alpha 1 antitrypsin, particularly liver diseases.