Enzyme-Activated H2S Precursors for Controlled Release
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Solution Overview
Problem
Current hydrogen sulfide (H2S) donors have limitations such as uncontrollable or fixed release rates, and some consume free thiols in biological systems, disrupting thiol redox balance. There is a need for H2S donors that can release H2S controllably and safely in vivo and in vitro without external stimuli or consumption of biological nutrients.
Innovation Solution
The development of precursor compounds that, when contacted with a hydrolyzing, oxidizing, reducing agent, or an enzyme, undergo cyclization via lactone or lactam formation to release hydrogen sulfide. These compounds are designed to mimic the endogenous production of H2S, providing a controlled and sustained release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional H2S donors are used, then H2S can be delivered to biological systems, but the release rate is uncontrollable or fixed and inflexible
Solution Approach 1:
The patent employs dynamic control of H2S release through enzymatic activation. The precursor compounds remain stable until encountered with specific enzymes (such as esterase, carboxylesterase, or butyrylcholinesterase) in the biological system, which then trigger controlled hydrolysis and H2S release. This enzymatic gating mechanism provides adaptive, controllable release rates that respond to physiological conditions rather than using fixed release mechanisms.
Solution Approach 2:
The invention introduces enzyme-mediated intermediaries to control H2S release. Rather than direct release from simple donors, the system uses enzyme-precursor interactions as an intermediary step. The enzymes act as biological mediators that recognize and activate specific precursor compounds, enabling controlled transformation and H2S generation in response to physiological signals.
2Adaptability or versatility
If thiol-activated H2S donors are used, then H2S release can be controlled, but free thiols are consumed which disrupts thiol redox balance
Solution Approach 1:
The patent replaces thiol-based activation with enzyme-mediated activation. Instead of requiring free thiols to trigger H2S release (which depletes cellular thiol pools and disrupts redox balance), the system uses enzymes such as esterases and carboxylesterases as intermediaries. These enzymes catalyze the hydrolysis of precursor compounds without consuming free thiols, thereby maintaining thiol redox homeostasis while still achieving controlled H2S release.
Solution Approach 2:
The invention substitutes the chemical mechanism (thiol-based activation) with a biological enzymatic mechanism. Rather than relying on chemical reactions between thiols and H2S donors, the system employs enzymatic catalysis to drive precursor activation. This substitution eliminates the harmful consumption of free thiols while preserving the desirable feature of controlled, conditional H2S release.
3Adaptability or versatility
If H2S donors requiring external stimuli (e.g., UV light) are used, then H2S release can be controlled, but harmful external stimuli are required
Solution Approach 1:
The patent enables self-service activation of H2S release through endogenous enzymes present in the biological system. The precursor compounds are designed to be activated by naturally occurring enzymes such as esterases, carboxylesterases, and butyrylcholinesterase that are already present in tissues and fluids. This eliminates the need for external stimuli like UV light, allowing the system to autonomously control H2S release in response to physiological conditions without exposing tissues to harmful external energy sources.
4Reliability
If slow and continuous H2S release is achieved to mimic endogenous production, then physiological compatibility is improved, but such donors are currently not available
Solution Approach 1:
The patent creates self-regulating H2S delivery systems that automatically adjust release rates to mimic endogenous production. The precursor compounds are designed to be activated by endogenous enzymes at rates that naturally match physiological H2S production patterns. This enzymatic self-regulation ensures slow, continuous release that adapts to tissue-specific enzyme levels and physiological conditions, achieving physiological compatibility without requiring complex external control mechanisms.
Solution Approach 2:
The invention modulates key parameters of H2S release by varying the precursor compound structure and enzymatic recognition properties. By changing parameters such as the ester linkage type, aromatic substituents, and molecular geometry of precursors, the system optimizes activation rates by endogenous enzymes to achieve physiologically relevant, slow continuous release patterns that mimic natural H2S production in different tissues.
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 proposed solution allows for a controlled and sustained release of hydrogen sulfide, mimicking endogenous production, which addresses the limitations of existing H2S donors. This approach ensures safe and effective delivery of H2S for medical, pharmaceutical, and research applications without disrupting biological thiol redox balance.
Implementation Method 1
contacting is conducted under conditions sufficient for cyclization of the precursor compound via lactone or lactam formation
Implementation Method 2
contacting (i) a hydrolyzing agent, an oxidizing agent, a reducing agent, or an enzyme, and (iia) a precursor compound
Implementation Method 3
contacting (i) a hydrolyzing agent, an oxidizing agent, a reducing agent, or an enzyme, and (iia) a precursor compound
Data Source
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AI summary
The present invention provides methods of forming hydrogen sulfide. The methods include contacting a precursor compound with an unmasking agent; wherein the precursor compound comprises a hydrogen sulfide releasing moiety and a masked nucleophile; and wherein the contacting is conducted under conditions sufficient for cyclization of the precursor compound via lactone or lactam formation; thereby releasing hydrogen sulfide from the precursor compound. Hydrogen sulfide precursor compounds according to Formula (I) are also described, as well as methods for treating diseases and conditions using hydrogen sulfide precursors.