Esterase-Sensitive and pH-Controlled Carbon Monoxide Prodrugs for Treating Systemic Inflammation

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Biomedical Engineering

Background:

• Developing effective carbon monoxide (CO) based therapeutics faces challenges due to limitations in safe and controllable delivery systems.
• Existing methods for CO delivery lack the precision required for therapeutic applications, hindering clinical translation.

Purpose of the Study:

• To design and synthesize novel organic carbon monoxide (CO) prodrugs.
• To engineer these prodrugs with dual-responsive endogenous triggers for controlled CO release.
• To evaluate the therapeutic potential of these CO prodrugs in preclinical models of inflammation.

Main Methods:

• Synthesis of novel organic CO prodrugs featuring dual-responsive endogenous triggers.
• In vitro assessment of CO release kinetics and biological activity.
• In vivo evaluation of anti-inflammatory efficacy in a lipopolysaccharide (LPS)-induced systemic inflammation model.

Main Results:

• A representative organic CO prodrug demonstrated significant anti-inflammatory effects in vitro.
• The developed CO prodrug exhibited potent therapeutic activity in a preclinical model of LPS-induced systemic inflammation.
• The prodrug design enabled controllable CO release, addressing a key bottleneck in CO-based therapy development.

Conclusions:

• Organic CO prodrugs with dual-responsive endogenous triggers represent a promising platform for developing safe and effective CO-based therapeutics.
• These novel CO prodrugs show potential as research tools and candidate compounds for treating systemic inflammation and related organ injuries.
• The successful development of these prodrugs overcomes critical delivery challenges, paving the way for clinical applications of CO in inflammatory diseases.