Cyclic Disulfide Tethering for Cysteine Pair Specificity
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Solution Overview
Problem
Current therapeutic molecules targeting cysteine residues often face challenges in specificity, leading to off-target reactions and potential toxicity, particularly when targeting pairs of cysteine residues.
Innovation Solution
The development of cyclic disulfides that can cross-link specific pairs of cysteine residues on proteins, enhancing specificity and stability, and potentially stabilizing protein structures to treat diseases such as neurodegenerative disorders and cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If highly reactive electrophiles are used to target cysteine residues, then potency is enhanced through irreversible inhibition, but off-target reactions with hundreds of nucleophilic residues occur leading to toxicity
Solution Approach 1:
The electrophile is segmented into two separate components: a warhead that forms a reversible adduct with the cysteine, and a second electrophilic group that subsequently reacts to form the irreversible covalent bond. This segmentation allows the first component to provide selectivity through reversible binding while the second component delivers the irreversible inhibition, thereby maintaining potency while reducing off-target reactions.
Solution Approach 2:
The reversible adduct formation occurs as a preliminary action before the irreversible covalent bond is formed. This preliminary reversible binding step allows the drug to selectively target and bind to the intended cysteine residue with high specificity before committing to irreversible inhibition, thereby reducing off-target reactions while maintaining potency.
2Reliability
If cyclic sulphenamides are used to target cysteine residues, then irreversible binding is achieved, but specificity depends on acidic environment (pH 4-6) which limits applicability
Solution Approach 1:
The invention changes the chemical parameters of the electrophilic moiety from cyclic sulphenamides (which require acidic pH 4-6) to alternative electrophiles such as alpha-halo ketones, alpha-halo aldehydes, or fluorinated compounds that remain reactive and selective across a broader pH range (pH 6-8), thereby maintaining specificity while improving environmental adaptability.
3Object-affected harmful factors
If low-reactivity acrylamide electrophiles are used to minimize off-target reactions, then off-target binding is reduced, but reactivity is insufficient for effective covalent bonding
Solution Approach 1:
The electrophile is segmented into two components: a first electrophilic group (such as alpha-halo ketone or alpha-halo aldehyde) that reacts rapidly and selectively with the cysteine thiolate to form a reversible adduct, and a second electrophilic group that subsequently reacts to form the irreversible covalent bond. This segmentation provides both high reactivity for effective bonding and selectivity for minimizing off-target binding.
Solution Approach 2:
The reaction proceeds through a continuous mechanism where the reversible adduct formation is followed immediately by irreversible covalent bond formation. This continuous action ensures that the high reactivity of the first electrophilic group is effectively utilized to form the stable covalent bond, while the reversible nature of the initial step maintains selectivity and minimizes off-target binding.
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
Cyclic disulfides significantly enhance the specificity of therapeutic molecules for pairs of cysteine residues over lone cysteine residues, offering a strategy to improve existing specificity and potentially stabilize proteins to treat various diseases.
Implementation Method 1
cyclic disulfides that can cross-link specific pairs of cysteine residues on proteins
Implementation Method 2
cross-linking the first Protein X to the second Protein X
Data Source
AI summary
Described herein are compounds and methods for tethering proteins. For example, dimers of Protein X listed in Table 1 are described, where the dimers are formed by the covalent bonding of a cysteine on the first monomer to a cysteine on the second monomer via a cyclic disulfide linker. The covalently attached dimers exhibit increased stabilization and can be used to treat neurodegenerative diseases (such as, for example, Parkinson's Disease, ALS, Alzheimer's Disease, Huntington's Disease, Epilepsy, Frontotemporal Dementia, and/or DMD), cancer, autoimmune disease, and/or Celiac disease.