Stem-Loop IL8 Aptamers for Stable Ocular Inhibition
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Solution Overview
Problem
There is an unmet need for inhibitors with high specificity and potency towards Interleukin-8 (IL8) that are effective in treating various ocular diseases, as existing treatments lack sufficient efficacy and specificity.
Innovation Solution
Development of aptamers with specific nucleic acid sequences that selectively bind to IL8, including its N-terminal domain, hydrophobic pocket, or N-loop, demonstrating high affinity and stability in the presence of heparan sulphate, and inhibiting IL8 activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used for IL8 inhibition, then treatment is available, but specificity and potency are insufficient
Solution Approach 1:
The patent uses aptamers as simplified copies or mimics of antibodies that bind to IL8. These aptamers are selected through SELEX to replicate the binding function of natural ligands while achieving high specificity and potency, thereby resolving the contradiction between treatment availability and therapeutic efficacy
Solution Approach 2:
The patent optimizes aptamer sequences and structures to achieve specific binding parameters (Kd < 0.5 nM) and stability characteristics. By systematically varying nucleotide sequences and selecting those with optimal binding parameters, the invention achieves both high specificity/potency and effective disease treatment
2Strength
If aptamers bind strongly to IL8, then inhibition potency increases, but binding stability in presence of heparan sulphate may decrease
Solution Approach 1:
The patent selects aptamers that bind to specific epitopes of IL8 (N-terminal domain, hydrophobic pocket, N-loop) rather than the GAG-binding site, effectively using these structural regions as intermediaries to achieve strong binding without competition from heparan sulphate. This epitope selection strategy allows simultaneous achievement of high affinity and stability in the presence of heparan sulphate
Solution Approach 2:
The patent focuses binding on specific local regions (epitopes) of the IL8 protein rather than general binding. By targeting specific structural domains (N-terminal domain, hydrophobic pocket, N-loop), the aptamers achieve localized high-affinity binding that is not disrupted by heparan sulphate, which competes for different binding sites
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 aptamers exhibit strong binding to IL8 with a dissociation constant (Kd) of less than 0.5 nM and maintain at least 75% binding in the presence of 10 μM heparan sulphate, effectively inhibiting IL8-related ocular diseases.
Implementation Method 1
a nucleic acid sequence that selectively binds to an epitope of IL8
Implementation Method 2
at least 75% of said aptamer remains bound to IL8 in a presence of 10 μM heparan sulphate
Data Source
AI summary
The application discloses methods and compositions for inhibiting functions associated with Interleukin-8 (IL8). The methods and compositions may involve the use of aptamers for binding to IL8 and preventing or reducing association of IL8 with CXCR1, CXCR2, or both. The methods and compositions may include one or more aptamers that bind to an N-terminal domain of IL8. The methods and compositions may include one or more aptamers that bind to a hydrophobic pocket of IL8. The methods and compositions may include one or more aptamers that bind to an N-loop of IL8. The methods and compositions may include one or more aptamers that bind to a GAG binding site of IL8. The application further provides anti-IL8 aptamers for the treatment of ocular diseases or disorders. In some cases, the anti-IL8 aptamers may have a stem-loop secondary structure.