Carbon monoxide-releasing molecules

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Structure of RuCl(gly)(CO)3, known as CORM-3. RuCl(gly)(CO)3.png
Structure of RuCl(gly)(CO)3, known as CORM-3.

Carbon monoxide-releasing molecules (CORMs) are chemical compounds designed to release controlled amounts of carbon monoxide (CO). CORMs are being developed as potential therapeutic agents to locally deliver CO to cells and tissues, thus overcoming limitations of CO gas inhalation protocols.

Contents

CO is best known for its toxicity in carbon monoxide poisoning at high doses. However, CO is a gasotransmitter and supplemental low dosage of CO has been linked to therapeutic benefits. Pre-clinical research has focused on CO's anti-inflammatory activity with significant applications in cardiovascular disease, oncology, transplant surgery, and neuroprotection. [1]

History

Therapeutic interest in CO dates back to the study of factitious airs (hydrocarbonate) in the 1790s by Thomas Beddoes, James Watt, James Lind, Humphry Davy, Tiberius Cavallo and many others. [2]

Nickel tetracarbonyl was the first carbonyl-complex used to achieve local delivery of CO and was the first CO delivery molecule suggested to have therapeutic potential in 1891. [2] The acronym CORM was coined in 2002, which marks the first modern biomedical and pharmaceutical initiative. [3] The enzymatic reaction of heme oxygenase inspired the development of synthetic CORMs.

The first synthetic CORMs were typically metal carbonyl complexes. A representative CORM that has been extensively characterized both from a biochemical and pharmacological view point is the ruthenium(II) complex Ru(glycinate)Cl(CO)3, commonly known as CORM-3. Therapeutic data pertaining to metallic CORMs are being reappraised to elucidate if observed effects are actually due to CO, or, if metal reactivity mediates physiological effects via thiol depletion, facilitating reduction, ion channel blockage, or redox catalysis. [4] [5] Despite questions pertaining to transition metals, pure CO gas and alternative non-metallic CO prodrugs and drug delivery devices have confirmed CO's therapeutic potential.

CORM classifications

Transition metal CORMs

The majority of therapeutically relevant CORMs are transition metal complexes primarily based on iron, molybdenum, ruthenium, manganese, cobalt, rhenium and others. [6]

PhotoCORMs

The release of CO from carrier agents can be induced photochemically. These carriers are called photoCORMs and include both metal complexes and metal-free (organic) compounds of various structural motifs which could be regarded as a special type of photolabile protecting group. [7]

ET-CORMs

Enzyme-triggered CORMs (ET-CORMs) have been developed to improve selective local delivery of CO. Some ET-CORM prodrugs are activated by esterase enzymes for site specific liberation of CO. [8]

CO prodrugs

Organic CORMs are being developed to overcome reactivity and certain toxicity limitations of inorganic CORMs.

Methylene chloride was the first organic CORM orally administered based on previous reports of carboxyhemoglobin formation via metabolism. The second organic CORM, CORM-A1 (sodium boranocarbonate), was developed based on a 1960s report of CO release from potassium boranocarbonate. [2]

In 2003, cyclic oxocarbons were suggested as a source for therapeutic CO including deltic acid, squaric acid, croconic acid, and rhodizonic acid and their salts. [9]

Recent years have seen increasing interests in organic CO prodrugs because of the need to consider drug developability issues in developing CO-based therapeutics. [10] These CO prodrugs have tunable release rate, triggered release, and the ability to release more than one payload from a single prodrug. [11]

Enzyme hybrids

Based on the synergism of the heme oxygenase system and CO delivery, a new molecular hybrid-CORM (HYCO) class emerged consisting of a conjoined HO-1 inducer and CORM species. One such HYCO includes a dimethyl fumarate moiety which activates NRF2 to thereby induce HO-1, whilst the CORM moiety also liberates CO. [12]

Carbon monoxide releasing materials

Carbon monoxide releasing materials (CORMAs) are essentially novel drug formulations and drug delivery platforms which have emerged to overcome the pharmaceutical limitations of most CORM species. [13] An exemplary CORMA developed by Hubbell consists of a formulation of micelles prepared from triblock copolymers with a CORM entity, which is triggered for release via addition of cysteine. Other CO-releasing scaffolds include polymers, peptides, silica nanoparticles, nanodiamond, magnetic nanoparticles, nanofiber gel, metallodendrimers, and CORM-protein (macromolecule) conjugates. [14] [15]

Other advanced drug delivery devices, such as encapsulated CORMs and extracorporeal membrane-inspired technologies, have been developed. [5]

Carboxyhemoglobin infusion

Carboxyhemoglobin can be infused to deliver CO. The most common approaches are based on polyethylene glycol PEGylated bovine carboxyhemoglobin and maleimide PEG conjugated human carboxyhemoglobin. [16]

Porphyrins

Porphyrin structures such as heme, hemin, and metallic protoporphyrin IX (PPIX) analogs (such as cobalt PPIX) have been deployed to induce heme oxygenase and subsequently undergo biotransformation to liberate CO, the inorganic ion, and biliverdin/bilirubin. [17] Some PPIX analogs such as tin PPIX, tin mesoporphyrin, and zinc PPIX, are heme oxygenase inhibitors.

Endogenous CO

HMOX is regarded as the main source of endogenous CO production, though other minor contributors have been identified in recent years. [18] CO is formed at a rate of 16.4 μmol/hour in the human body, ~86% originating from heme via heme oxygenase and ~14% from non-heme sources including: photooxidation, lipid peroxidation, and xenobiotics. [19] The average carboxyhemoglobin (CO-Hb) level in a non-smoker is under 3% CO-Hb (whereas a smoker may reach levels near 10% CO-Hb), [20] though geographic location, occupation, health and behavior are contributing variables.

Heme oxygenase

In the late 1960s Rudi Schmid characterized the enzyme that facilitates the reaction for heme catabolism, thereby identifying the heme oxygenase (HMOX) enzyme.

HMOX is a heme-containing member of the heat shock protein (HSP) family identified as HSP32. Three isoforms of HMOX have been identified to date including the stress-induced HMOX-1 and constitutive HMOX-2. HMOX-1 is considered a cell rescue protein which is induced in response to oxidative stress and numerous disease states. Furthermore, HMOX-1 is induced by countless molecules including statins, hemin, and natural products. [21] [22]

HMOX catalyzes the degradation of heme to biliverdin/bilirubin, ferrous ion, and CO. Though present throughout the body, HO has significant activity in the spleen in the degradation of hemoglobin during erythrocyte recycling (0.8% of the erythrocyte pool per day), which accounts for ~80% of heme derived endogenous CO production. The majority of the remaining 20% of heme derived CO production is attributed to hepatic catabolism of hemoproteins (myoglobin, cytochromes, catalase, peroxidases, soluble guanylate cyclase, nitric oxide synthase) and ineffective erythropoiesis in bone marrow. [23]

The enzymatic velocity and catalytic activity of HMOX can be enhanced by a plethora of dietary substances and xenobiotics to increase CO production.

Minor CO sources

The formation of CO from lipid peroxidation was first reported in the late 1960s and is regarded as a minor contributor to endogenous CO production. [24] [25] Other contributing sources include: the microbiome, cytochrome P450 reductase, human acireductone dioxygenase, tyrosinase, lipid peroxidation, alpha-keto acids, and other oxidative and redox mechanisms. [18]

CO pharmacology

Carbon monoxide is one of three gaseous signaling molecules alongside nitric oxide and hydrogen sulfide. These gases are collectively referred to as gasotransmitters. CO is a classical example of hormesis such that low-dose is essential and beneficial, whereas an absence or excessive exposure to CO can be toxic.

Signaling

The first evidence of CO as a signaling molecule occurred upon observation of CO stimulating soluble guanylate cyclase and subsequent cyclic guanosine monophosphate (cGMP) production to serve as a vasodilator in vascular smooth muscle cells. The anti-inflammatory effects of CO are attributed to activation of the p38 mitogen-activated protein kinase (MAPK) pathway. While CO commonly interacts with the ferrous iron atom of heme in a hemoprotein, [26] it has been demonstrated that CO activates calcium-dependent potassium channels by engaging in hydrogen-bonding with surface histidine residues. [18] [27]

CO may have an inhibitory effect on numerous proteins including cytochrome P450 and cytochrome c oxidase. [28]

Pharmacokinetics

CO has approximately 210x greater affinity for hemoglobin than oxygen. The equilibrium dissociation constant for the reaction Hb-CO ⇌ Hb + CO strongly favours the CO complex, thus the release of CO for pulmonary excretion generally takes some time.

Based on this binding affinity, blood is essentially an irreversible sink for CO and presents a therapeutic challenge for the delivery of O2 to cells and tissues.

CO is considered non-reactive in the body and primarily undergoes pulmonary excretion. [29]

Related Research Articles

<span class="mw-page-title-main">Carbon monoxide</span> Colourless, odourless, tasteless and toxic gas

Carbon monoxide is a poisonous, flammable gas that is colorless, odorless, tasteless, and slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simplest carbon oxide. In coordination complexes, the carbon monoxide ligand is called carbonyl. It is a key ingredient in many processes in industrial chemistry.

<span class="mw-page-title-main">Myoglobin</span> Iron and oxygen-binding protein

Myoglobin is an iron- and oxygen-binding protein found in the cardiac and skeletal muscle tissue of vertebrates in general and in almost all mammals. Myoglobin is distantly related to hemoglobin. Compared to hemoglobin, myoglobin has a higher affinity for oxygen and does not have cooperative binding with oxygen like hemoglobin does. Myoglobin consists of non-polar amino acids at the core of the globulin, where the heme group is non-covalently bounded with the surrounding polypeptide of myoglobin. In humans, myoglobin is found in the bloodstream only after muscle injury.

An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples this electron transfer with the transfer of protons (H+ ions) across a membrane. Many of the enzymes in the electron transport chain are embedded within the membrane.

<span class="mw-page-title-main">Heme</span> Chemical coordination complex of an iron ion chelated to a porphyrin

Heme, or haem, is a ring-shaped iron-containing molecular component of hemoglobin, which is necessary to bind oxygen in the bloodstream. It is composed of four pyrrole rings with 2 vinyl and 2 propionic acid side chains. Heme is biosynthesized in both the bone marrow and the liver.

<span class="mw-page-title-main">Carbon monoxide poisoning</span> Toxic effects of carbon monoxide

Carbon monoxide poisoning typically occurs from breathing in carbon monoxide (CO) at excessive levels. Symptoms are often described as "flu-like" and commonly include headache, dizziness, weakness, vomiting, chest pain, and confusion. Large exposures can result in loss of consciousness, arrhythmias, seizures, or death. The classically described "cherry red skin" rarely occurs. Long-term complications may include chronic fatigue, trouble with memory, and movement problems.

Carboxyhemoglobin is a stable complex of carbon monoxide and hemoglobin (Hb) that forms in red blood cells upon contact with carbon monoxide. Carboxyhemoglobin is often mistaken for the compound formed by the combination of carbon dioxide (carboxyl) and hemoglobin, which is actually carbaminohemoglobin. Carboxyhemoglobin terminology emerged when carbon monoxide was known by its historic name, "carbonic oxide", and evolved through Germanic and British English etymological influences; the preferred IUPAC nomenclature is carbonylhemoglobin.

<span class="mw-page-title-main">Cytochrome P450</span> Class of enzymes

Cytochromes P450 are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases.However, they are not omnipresent; for example, they have not been found in Escherichia coli. In mammals, these enzymes oxidize steroids, fatty acids, xenobiotics, and participate in many biosyntheses. By hydroxylation, CYP450 enzymes convert xenobiotics into hydrophilic derivatives, which are more readily excreted.

<span class="mw-page-title-main">Nitric oxide synthase</span> Enzyme catalysing the formation of the gasotransmitter NO(nitric oxide)

Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS and nNOS. The inducible isoform, iNOS, involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the proximate cause of septic shock and may function in autoimmune disease.

An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 (as in air) to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14.

<span class="mw-page-title-main">HMOX1</span> Mammalian protein found in Homo sapiens

HMOX1 is a human gene that encodes for the enzyme heme oxygenase 1. Heme oxygenase mediates the first step of heme catabolism, it cleaves heme to form biliverdin.

<span class="mw-page-title-main">Heme oxygenase</span> Class of enzymes

Heme oxygenase, or haem oxygenase, is an enzyme that catalyzes the degradation of heme to produce biliverdin, ferrous iron, and carbon monoxide.

Gasotransmitters is a class of neurotransmitters. The molecules are distinguished from other bioactive endogenous gaseous signaling molecules based on a need to meet distinct characterization criteria. Currently, only nitric oxide, carbon monoxide, and hydrogen sulfide are accepted as gasotransmitters. According to in vitro models, gasotransmitters, like other gaseous signaling molecules, may bind to gasoreceptors and trigger signaling in the cells.

Iron-binding proteins are carrier proteins and metalloproteins that are important in iron metabolism and the immune response. Iron is required for life.

<span class="mw-page-title-main">Protoporphyrin IX</span> Chemical compound

Protoporphyrin IX is an organic compound, classified as a porphyrin, that plays an important role in living organisms as a precursor to other critical compounds like heme (hemoglobin) and chlorophyll. It is a deeply colored solid that is not soluble in water. The name is often abbreviated as PPIX.

<span class="mw-page-title-main">Formate dehydrogenase</span>

Formate dehydrogenases are a set of enzymes that catalyse the oxidation of formate to carbon dioxide, donating the electrons to a second substrate, such as NAD+ in formate:NAD+ oxidoreductase (EC 1.17.1.9) or to a cytochrome in formate:ferricytochrome-b1 oxidoreductase (EC 1.2.2.1). This family of enzymes has attracted attention as inspiration or guidance on methods for the carbon dioxide fixation, relevant to global warming.

<span class="mw-page-title-main">NFE2L2</span> Human protein and coding gene

Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene. NRF2 is a basic leucine zipper (bZIP) protein that may regulate the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation, according to preliminary research. In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins. NRF2 induces the expression of heme oxygenase 1 in vitro leading to an increase in phase II enzymes. NRF2 also inhibits the NLRP3 inflammasome.

<span class="mw-page-title-main">HMOX2</span> Protein-coding gene in the species Homo sapiens

Heme oxygenase 2 is an enzyme that in humans is encoded by the HMOX2 gene.

<span class="mw-page-title-main">Dioxygenase</span> Class of enzymes

Dioxygenases are oxidoreductase enzymes. Aerobic life, from simple single-celled bacteria species to complex eukaryotic organisms, has evolved to depend on the oxidizing power of dioxygen in various metabolic pathways. From energetic adenosine triphosphate (ATP) generation to xenobiotic degradation, the use of dioxygen as a biological oxidant is widespread and varied in the exact mechanism of its use. Enzymes employ many different schemes to use dioxygen, and this largely depends on the substrate and reaction at hand.

In chemistry, decarbonylation is a type of organic reaction that involves the loss of carbon monoxide (CO). It is often an undesirable reaction, since it represents a degradation. In the chemistry of metal carbonyls, decarbonylation describes a substitution process, whereby a CO ligand is replaced by another ligand.

<span class="mw-page-title-main">Esther Killick</span> British physiologist

Esther Margaret Killick was an English physiologist who was a professor of physiology at the London School of Medicine for Women from 1941 until her death in 1960. Her main research interests lay in respiratory physiology and carbon monoxide poisoning.

References

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