Carbon‐Monoxide‐Releasing Molecules for the Delivery of Therapeutic CO In Vivo

García‐Gallego, Sandra; Bernardes, Gonçalo J. L.

doi:10.1002/anie.201311225

Cited by 298 publications

(234 citation statements)

References 75 publications

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“…Unlike most common drugs whose pharmacological action is dependent on their interaction with a macromolecular target and whose potency is dictated by the stability of the drug-target complex, CORMs exert their therapeutic action via the liberated CO molecules. [1][2][3][4][5] However, apart from the common scientific consensus that CORM-based therapy should not lead to significant carboxyhemoglobin (COHb) formation and to the inhibition of respiratory enzymes that are sensitive to CO, it is questionable whether CORMs should release CO slowly or rapidly and what kinetics of CO release is most advantageous for therapeutic applications. There are only few reports clearly showing the advantages of CORMs slowly releasing CO over those releasing CO instantly 6,7 and they relate to the anti-platelet effects of CORMs.…”

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confidence: 99%

Modified biovectors for the tuneable activation of anti-platelet carbon monoxide release

et al. 2017

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This communication describes the anti-platelet effects of a new class of cis-rhenium(II)-dicarbonyl-vitamin B 12 complexes with tuneable CO releasing properties.Carbon-monoxide releasing molecules (CORMs) represent an innovative class of compounds which attract interest due to their potential therapeutic utility. Unlike most common drugs whose pharmacological action is dependent on their interaction with a macromolecular target and whose potency is dictated by the stability of the drug-target complex, CORMs exert their therapeutic action via the liberated CO molecules. [1][2][3][4][5] However, apart from the common scientific consensus that CORM-based therapy should not lead to significant carboxyhemoglobin (COHb) formation and to the inhibition of respiratory enzymes that are sensitive to CO, it is questionable whether CORMs should release CO slowly or rapidly and what kinetics of CO release is most advantageous for therapeutic applications. There are only few reports clearly showing the advantages of CORMs slowly releasing CO over those releasing CO instantly 6,7 and they relate to the anti-platelet effects of CORMs. Furthermore, it has proved chemically challenging to fine-tune the activation and the rate of CO release within a family of structurally similar CORM compounds. For all of these reasons, versatile classes of CORMs with tuneable release properties affording anti-platelet activity are highly desired for tackling these open questions in systematic structure-activity relationship studies. Such studies will facilitate the development of CORMs with optimal antiplatelet activity. -(CO) 2 fragment. This approach seemed to be reasonable because small variations in the coordination sphere of rhenium complexes have profound consequences on the electrochemistry, water stability and CO releasing properties of the dicarbonyl core.17 B 12 appeared to be attractive as ligand for the rhenium-based CORM entity mainly because of two reasons: (a) its cellular uptake properties can be exploited to deliver therapeutic agents specifically at disease sites; 18-20 (b) the electronic properties at the cobalt center can be selectively modified by introducing structural modifications at the corrin-p-system. 21-24Having the general design of the B 12 -ReCORMs derivatives in mind (Scheme 1), we synthesized and studied first a series of Scheme 1 General design concept for the tuneable activation of CORMbiovectors conjugates.

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Modified biovectors for the tuneable activation of anti-platelet carbon monoxide release

et al. 2017

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“…[13][14][15] Although several stimulus-responsive composites have been investigated in biological applications at the nanoscale,there have been few reports of functionalizing the composites in living cells. [16,17] Delivery of carbon monoxide (CO) into living cells represents ac hallenging task [18] and could possibly be achieved by applying protein assemblies involving metal complexes.M etal carbonyl complexes have been used as carbon-monoxide-releasing molecules (CORMs) for both in vitro and in vivo delivery of CO for the purpose of investigating the function of CO as an intracellular signaling molecule. …”

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A Photoactive Carbon‐Monoxide‐Releasing Protein Cage for Dose‐Regulated Delivery in Living Cells

et al. 2015

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Protein cages can serve as bioinorganic molecular templates for functionalizing metal compounds to regulate cellular signaling. We succeeded in developing a photoactive CO-releasing system by constructing a composite of ferritin (Fr) containing manganese-carbonyl complexes. When Arg52 adjacent to Cys48 of Fr is replaced with Cys, the Fr mutant stabilizes the retention of 48 Mn-carbonyl moieties, which can release the CO ligands under light irradiation, although wild-type Fr retains very few Mn moieties. The amount of released CO is regulated by the extent of irradiation. This could reveal an optimized dose for cooperatively activating the nuclear factor κB (NF-κB) in mammalian cells and the tumor necrosis factor α (TNF-α). These results suggest that construction of a CO-releasing protein cage will advance of research in CO biology.

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“…For the controlled delivery and release of the toxic gas in aqueous environments, carbon monoxide-releasing molecules (CORMs) have proven to be the most promising for therapeutic usage (27,28). Transition metal carbonyl complexes are the most prominent CORMs because they can be triggered via light, solvent exchange on the metal coordination sphere, and enzymes (29,30).…”

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confidence: 99%

Bactericidal Effect of a Photoresponsive Carbon Monoxide-Releasing Nonwoven against Staphylococcus aureus Biofilms

Klinger-Strobel

Gläser

Makarewicz

et al. 2016

Antimicrob Agents Chemother

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Staphylococcus aureus is a leading pathogen in skin and skin structure infections, including surgical and traumatic infections that are associated with biofilm formation. Because biofilm formation is accompanied by high phenotypic resistance of the embedded bacteria, they are almost impossible to eradicate by conventional antibiotics. Therefore, alternative therapeutic strategies are of high interest. We generated nanostructured hybrid nonwovens via the electrospinning of a photoresponsive carbon monoxide (CO)-releasing molecule [CORM-1, Mn 2 (CO) 10 ] and the polymer polylactide. This nonwoven showed a CO-induced antimicrobial activity that was sufficient to reduce the biofilm-embedded bacteria by 70% after photostimulation at 405 nm. The released CO increased the concentration of reactive oxygen species (ROS) in the biofilms, suggesting that in addition to inhibiting the electron transport chain, ROS might play a role in the antimicrobial activity of CORMs on S. aureus. The nonwoven showed increased cytotoxicity on eukaryotic cells after longer exposure, most probably due to the released lactic acid, that might be acceptable for local and short-time treatments. Therefore, CO-releasing nonwovens might be a promising local antimicrobial therapy against biofilm-associated skin wound infections. Staphylococcus aureus, both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA), is the leading pathogen in skin and skin structure infections (SSSIs), including surgical and traumatic infections (1, 2). S. aureus has developed a highly effective mechanism to invade tissues and evade the immune system by biofilm formation and intracellular persistence. This can result in chronic and recurring SSSI, particularly in patients with comorbidities such as diabetes mellitus (e.g., diabetic foot syndrome). Noneradicable S. aureus SSSI can be the focus of S. aureus bacteremia, which has a mortality of up to 30% (3). In the United States, community-acquired MRSA has emerged as one of the leading causes of community-acquired SSSI (2).Biofilms are sessile matrix-embedded microbial communities that colonize nearly all artificial and natural surfaces. They are thought to be present in more than 80% of all nosocomial bacterial infections (4). Compared to their planktonic counterparts, bacteria embedded in a biofilm benefit from the protective properties of the matrix, conveying up to 1,000-fold-higher resistance to antibiotics (5). The enhanced phenotypic resistance (correctly termed tolerance) of biofilms is caused mainly by decreased growth rates and metabolically inactive persister cells (a protected phenotypic state) (6). Most antibiotics inhibit metabolic processes in the cell, such as replication (e.g., fluoroquinolones), transcription (e.g., rifampin) or translation (e.g., aminoglycosides and macrolides), and therefore they become ineffective in these persister cells. Altered microenvironments (7) and enzymes hydrolyzing or modifying the antimicrobials that are enriched within the matrix are additio...

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Carbon‐Monoxide‐Releasing Molecules for the Delivery of Therapeutic CO In Vivo

Cited by 298 publications

References 75 publications

Modified biovectors for the tuneable activation of anti-platelet carbon monoxide release

Modified biovectors for the tuneable activation of anti-platelet carbon monoxide release

A Photoactive Carbon‐Monoxide‐Releasing Protein Cage for Dose‐Regulated Delivery in Living Cells

Bactericidal Effect of a Photoresponsive Carbon Monoxide-Releasing Nonwoven against Staphylococcus aureus Biofilms

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