Design, Synthesis, and Functional Evaluation of CO‐Releasing Molecules Triggered by Penicillin G Amidase as a Model Protease

Abstract

Protease-triggered CO-releasing molecules (CORMs) were developed. The viability of the approach was demonstrated through the synthesis of compounds consisting of an η(4) -oxydiene-Fe(CO)3 moiety connected to a penicillin G amidase (PGA)-cleavable unit through a self-immolative linker. The rate of PGA-induced hydrolysis was investigated by HPLC analysis and the subsequent CO release was quantitatively assessed through headspace gas chromatography. In an in vitro assay with human endothelial cells, typical biological effects of CO, that is, inhibition of the inflammatory response and the induction of heme oxygenase-1 expression, were observed only upon co-administration of the CORM and PGA. This work forms a promising basis for the future development of protease-specific CORMs for potential medicinal applications.

Toward Carbon Monoxide–Based Therapeutics: Critical Drug Delivery and Developability Issues

“…In 2015, to further address the site-specific targeting issue, protease-activated ET-CO-RMs ( 6 and 7 ) were synthesized. 83 This type of ET-CO-RMs comprise of a protease-specific peptide, which is used as a targeting moiety, a self-immolative linker, which was used to tune the rate of CO release, and an oxycyclohexadiene–Fe(CO) 3 moiety, which would release CO after dissociation of the iron complex from the diene moiety. By using different self-immolative linkers, various release rates were achieved.…”

Cyanine‐Flavonol Hybrids for Near‐Infrared Light‐Activated Delivery of Carbon Monoxide

“…[4,13,14] Generally,t hese CORMs rely on enzymes as the release triggerso ro nasolvent-mediated ligand exchange reaction in aqueous media, methods that exhibit poor spatial and temporal control over the release profile. [15,16] Furthermore, the metal backbonel eft upon CO releasefrom these metal-carbonyl complexes can lead to uncontrolledr eactions with adjacent cells, resulting in their damage and am ajor barrier to in vivo CORM applications. [6] Transition-metal-free light-triggered CORMs( photoCORMs) have recently appeared with the promise of circumventing these challenges.…”

Design of biomaterials for intracellular delivery of carbon monoxide

“…[46][47][48][49][50][51][52] This concept is based on enzymatic reactions of intracellular enzymes with ligands of CORMs designed as esterase-reactive moieties. The first examples of ET-CORMs were acyloxybutadiene-Fe(CO) 3 complexes.…”

“…The development of protease-triggered CORMs has also been recently reported on. 50 The CORMs consist of a peptidase-specific oligopeptide, a self-immolative linker, and an oxycyclohexadiene-Fe(CO) 3 (Fig. 5e).…”