Segmented ACE2 Fragments for Glomerular Filtration
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Solution Overview
Problem
Current approaches to treating kidney diseases, such as diabetic and non-diabetic chronic kidney disease, are limited by the large molecular size of angiotensin-converting enzyme 2 (ACE2), which prevents it from being filtered through the glomerulus, thereby failing to effectively target the kidney and reduce Angiotensin II levels locally.
Innovation Solution
Development of shorter ACE2 fragments with molecular weights less than 70 kD, such as ACE2 1-619 and 1-605, that are filterable through the glomerulus, conjugated with low molecular weight fusion polypeptides like Fc, albumin, or lysozyme to enhance kidney delivery and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If full-length ACE2 is used, then ACE2 biological activity is maintained, but the large molecular size prevents glomerular filtration and kidney targeting
Solution Approach 1:
The full-length ACE2 protein is divided into smaller fragments (e.g., amino acids 1-619, 1-605, 1-580, or 1-560) that retain the essential catalytic domain while reducing molecular size below the glomerular filtration threshold, enabling kidney targeting through filtration
2Ease of operation
If shorter ACE2 fragments are used, then glomerular filtration and kidney delivery are enabled, but ACE2 biological activity may be reduced
Solution Approach 1:
The shorter ACE2 fragments are designed to preserve the catalytic domain with critical amino acid residues (including zinc-binding motifs and substrate-binding regions) while removing non-essential regions, ensuring that local functional quality is maintained despite overall size reduction
3Duration of action of moving object
If ACE2 is conjugated with fusion polypeptides, then half-life is extended, but molecular size increases
Solution Approach 1:
The ACE2 fragment is combined with fusion polypeptides (such as Fc, albumin, or lysozyme) to create a composite molecule that leverages the long circulation half-life of the fusion partner while maintaining the ACE2 catalytic function, achieving both extended duration and adequate size for filtration
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 shorter ACE2 fragments effectively lower Angiotensin II levels and increase Angiotensin (1-7) levels in the kidney, providing renoprotective effects and improving kidney function, while also being suitable for chronic use with extended half-life through fusion technologies.
Implementation Method 1
An important biological effect of ACE2 is to convert AngII(1-8) to Ang(1-7), a process that tends to lower AngII(1-8) and therefore prevents the potentially detrimental actions of this peptide
Implementation Method 2
The large molecular size of recombinant ACE2 renders it non-filterable by a normal glomerulus or in early forms of kidney disease... Therefore, to circumvent this limitation we designed shorter forms of ACE2 that are much more suitable to treat kidney disease
Data Source
AI summary
Disclosed are variants of ACE2, pharmaceutical compositions comprising the variants of ACE2, and treatment methods for reducing Angiotensin II (1-8) plasma levels and/or increasing Angiotensin (1-7) plasma levels in a subject in need thereof. The disclosed variants of ACE2 may include polypeptide fragments of ACE2 having ACE2 activity for converting AngII(1-8) to Ang(1-7). Suitable subjects suitable for the disclosed methods of treatment may include subjects having or at risk for developing diabetic and non-diabetic chronic kidney disease, acute renal failure and its prevention, chronic kidney disease, severe hypertension, scleroderma and its skin, pulmonary, kidney and hypertensive complications, malignant hypertension, renovascular hypertension secondary to renal artery stenosis, idiopathic pulmonary fibrosis, liver fibrosis such as in liver cirrhosis patients, an aortic aneurysm, cardiac fibrosis and remodeling, left ventricular hypertrophy, and an acute stroke.