Opsin-Binding Ligands for Retinal Protein Folding Stability
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Solution Overview
Problem
Current treatments for ophthalmic diseases such as retinitis pigmentosa and age-related macular degeneration face challenges due to improper protein folding of opsin, leading to visual cycle disruptions and toxic product accumulation, which can cause vision loss and toxicity during surgical procedures.
Innovation Solution
Development of small molecule ligands that non-covalently bind to opsin, inhibiting 11-cis-retinal binding and promoting proper protein folding and trafficking, thereby reducing the formation of toxic visual cycle products and minimizing light-induced toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If chemical chaperones (e.g., glycerol, trimethylamine oxide) are used to stabilize misfolded opsin proteins, then protein folding is improved, but high dosages are required that cause toxic side effects
Solution Approach 1:
The patent introduces specific retinoid compounds (e.g., 11-cis-retinal, synthetic retinoids) as intermediary molecules that selectively bind to misfolded opsin proteins. These retinoids act as pharmacological chaperones that mediate the stabilization process, allowing the drugs to specifically target and stabilize mutant opsins without requiring high concentrations of non-specific chemical chaperones, thereby reducing toxic side effects while improving protein folding stability
Solution Approach 2:
The patent modifies the chemical structure of retinoid compounds to optimize their binding affinity and selectivity for misfolded opsin proteins. By changing parameters such as molecular structure, binding constant, and specificity, the invention develops retinoid derivatives that can stabilize mutant opsins at lower concentrations, thus improving folding stability while minimizing toxicity compared to conventional chemical chaperones
2Stability of the object's composition
If retinoid compounds are used to stabilize mutant opsin proteins, then protein stability is improved, but the visual cycle is disrupted leading to toxic product accumulation
Solution Approach 1:
The patent employs retinoid compounds at controlled, sub-saturating concentrations that provide sufficient stabilization of mutant opsin proteins without completely blocking the visual cycle. This partial action approach allows enough retinoid binding to stabilize misfolded proteins and improve their trafficking to the cell membrane, while leaving sufficient unbound retinoid available to maintain normal visual cycle function and prevent toxic product accumulation
Solution Approach 2:
The patent uses synthetic retinoid compounds that mimic the structure and binding properties of natural 11-cis-retinal. These retinoid copies can bind to and stabilize mutant opsin proteins without fully engaging the visual cycle, allowing stabilization of misfolded proteins while preserving sufficient natural retinoid availability for normal visual function and preventing toxic byproduct accumulation
3Object-generated harmful factors
If 11-cis-retinal binding is inhibited to prevent toxic product formation, then toxic product accumulation is reduced, but rhodopsin formation is impaired affecting vision
Solution Approach 1:
The patent utilizes retinoid compounds at optimized concentrations that provide partial inhibition of 11-cis-retinal binding to mutant opsin. This partial inhibition is sufficient to reduce toxic product accumulation from misfolded proteins while leaving enough binding capacity intact to maintain adequate rhodopsin formation and preserve visual function. The dosage and compound specificity are tuned to achieve this balance between reducing toxicity and maintaining vision
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 ligands effectively reduce the accumulation of toxic visual cycle products, prevent photoreceptor cell death, and alleviate vision loss associated with improper opsin folding and light exposure, offering a treatment for various ophthalmic conditions including retinitis pigmentosa and age-related macular degeneration.
Implementation Method 1
small molecule ligands that non-covalently bind to opsin, inhibiting 11-cis-retinal binding and promoting proper protein folding and trafficking
Implementation Method 2
inhibiting 11-cis-retinal binding and promoting proper protein folding and trafficking, thereby reducing the formation of toxic visual cycle products
Implementation Method 3
reducing the formation of toxic visual cycle products
Data Source
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AI summary
Compounds and compositions of said compounds along with methods of use of compounds are disclosed for treating ophthalmic conditions related to mislocalization of opsin proteins, the misfolding of mutant opsin proteins and the production of toxic visual cycle products that accumulate in the eye. Compounds and compositions useful in the these methods, either alone or in combination with other therapeutic agents, are also described.