Monomeric IL-37 Polypeptide Mutations Prevent Dimerization
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Solution Overview
Problem
Current anti-inflammatory compositions and treatments for inflammatory diseases lack effectiveness in managing uncontrolled inflammatory responses and tissue damage, as the relationship between the structure, function, and regulation of IL-37 activity is not fully understood, leading to limitations in therapeutic options.
Innovation Solution
Development of a monomeric anti-inflammatory polypeptide with specific mutations or modifications that reduce its capacity to form dimers, specifically targeting residues 71 to 74, 78, 80, 83 to 88, and 184, allowing for enhanced anti-inflammatory properties without the efficacy loss at high concentrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL-37 is used for anti-inflammatory treatment, then it can suppress inflammation through receptor binding, but it forms homodimers which reduces its effectiveness at high concentrations
Solution Approach 1:
The patent applies segmentation by introducing mutations at the dimer interface (residues 71-74, 78, 80, 83-88, and 184) to divide the homodimeric structure into monomeric units. This prevents the formation of inactive homodimers while preserving the anti-inflammatory function through receptor binding, thereby maintaining effectiveness across a wider concentration range.
Solution Approach 2:
The patent changes the physical-chemical parameters of the IL-37 protein by introducing specific amino acid mutations at the dimer interface. These parameter changes (substituting residues involved in dimerization) transform the protein from a dimerizing form to a monomeric form, improving its therapeutic reliability without sacrificing its biological activity.
2Reliability
If mutations are introduced to prevent dimer formation, then anti-inflammatory activity is enhanced at high concentrations, but the structural integrity may be affected
Solution Approach 1:
The patent applies local quality by introducing mutations only at specific local regions (the dimer interface residues 71-74, 78, 80, 83-88, and 184) rather than throughout the entire protein structure. This localized modification prevents dimer formation while preserving the overall structural integrity and functional domains of the IL-37 protein.
Solution Approach 2:
The patent converts the potentially harmful effect of uncontrolled dimer formation into a benefit by strategically designing mutations that prevent dimerization. This transforms the dimer interface region from a source of therapeutic limitation into a controlled feature that enhances monomeric stability and therapeutic effectiveness.
3Adaptability or versatility
If current anti-inflammatory compositions are used, then treatment options are available, but they lack effectiveness in managing uncontrolled inflammatory responses
Solution Approach 1:
The patent creates a universally applicable therapeutic agent by engineering IL-37 variants that maintain their anti-inflammatory function across diverse inflammatory conditions. The monomeric variants demonstrate enhanced versatility and reliability in managing uncontrolled inflammatory responses while preserving the ability to bind receptors and suppress pro-inflammatory cytokines.
Data Source
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AI summary
This invention relates to polypeptides, including variants of interleukin-37 (IL-37), and related therapeutics and compositions. The invention also relates to the use of the polypeptides and compositions in methods of treating inflammatory diseases or conditions. The present invention provides a monomeric anti-inflammatory polypeptide comprising an amino acid sequence of an IL-37 monomer, the amino acid sequence having a mutation or modification for preventing the anti-inflammatory peptide from forming a homodimer.