Carbon monoxide-releasing molecules
Carbon monoxide-releasing molecules are chemical compounds designed to release controlled amounts of carbon monoxide. CORMs are being developed as potential therapeutic agents to locally deliver CO to cells and tissues, thus overcoming limitations of CO gas inhalation protocols.
CO is best known for its toxicity in carbon monoxide poisoning at high doses. However, CO is among endogenous gaseous signaling molecules and low dosing 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.
The majority of CO produced in mammals originates from the degradation of heme by the three isoforms of heme oxygenase, whereby HO-1 is induced by oxidative stress, CO, and an array of xenobiotics. HO-2 and HO-3 are constitutive. Other endogenous sources may include lipid peroxidation,
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 complex RuCl3, commonly known as CORM-3.
CORM classifications
The simplest source of CO is from a combustion reaction via burning sources such as fossil fuels or fire wood. Sources releasing CO upon thermal decomposition or combustion are generally not considered CORMs.Transition metal CORMs
The majority of therapeutically relevant CORMs are transition metal complexes primarily based on iron, molybdenum, ruthenium, manganese, cobalt, and rheniumPhotoCORMs
The release of CO from carrier agents can be induced photochemically. These carriers are called photoCORMs and include both metal complexes and metal-free compounds of various structural motifs which could be regarded as a special type of photolabile protecting group.ET-CORMs
Enzyme-triggered 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.Organic CORMs
Organic small molecules are being developed to overcome 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, was developed based on a 1960s report of CO release from potassium boranocarbonate.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.
Organic CO prodrugs
Recent years have seen increasing interests in organic CO prodrugs because of the need to consider drug developability issues in developing CO-based therapeutics. These CO prodrugs have tunable release rate, triggered release, and the ability to release more than one payload from a single prodrug.Enzyme hybrids
Based on the synergism of the heme oxygenase system and CO delivery, a new molecular hybrid-CORM 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.Carbon monoxide releasing materials
Carbon monoxide releasing materials are essentially novel drug formulations and drug delivery platforms which have emerged to overcome the pharmaceutical limitations of most CORM species. 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 conjugates.Carboxyhemoglobin infusion
can be infused to deliver CO. The most common approaches are based on polyethylene glycol -lyated bovine carboxyhemoglobin and maleimide PEG conjugated human carboxyhemoglobin.Porphyrins
structures such as heme, hemin, and metallic protoporphyrin IX analogs have been deployed to induce heme oxygenase and subsequently undergo biotransformation to liberate CO, the inorganic ion, and biliverdin/bilirubin. Some PPIX analogs such as tin PPIX, tin mesoporphyrin, and zinc PPIX, are heme oxygenase inhibitors.Endogenous CO
In the late 1960's Tenhunen demonstrated an enzymatic reaction for heme catabolism thereby identifying the heme oxygenase enzyme. HO is the main source of endogenous CO production, though other minor contributors have been identified in recent years. 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. The average carboxyhemoglobin level in a non-smoker is between 0.2% and 0.85% CO-Hb, though geographic location, occupation, health and behavior are contributing variables.Enzymes
Heme oxygenase
is a heme-containing member of the heat shock protein family identified as HSP32. Three isoforms of HO have been identified to date including the stress-induced HO-1 and constitutive HO-2 and HO-3. HO-1 is considered a cell rescue protein which is induced in response to oxidative stress and numerous disease states. Furthermore, HO-1 is induced by countless molecules including statins, hemin, and natural products.HO 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, 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 and ineffective erythropoiesis in bone marrow.
Lipid peroxidation
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.CO pharmacology
is one of three gaseous signaling molecules alongside nitric oxide and hydrogen sulfide. These gases are collectively referred to as gasotransmitters.Signaling
The first evidence of CO as a signaling molecule occurred upon observation of CO stimulating soluble guanylate cyclase and subsequent cyclic guanosine monophosphate 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 pathway. While CO commonly interacts with the iron atom of heme in a hemoprotein, it has been demonstrated that CO activates calcium-dependent potassium channels by engaging in hydrogen-bonding with surface histidine residues.CO has an inhibitory effect on numerous proteins including cytochrome P450 and cytochrome c oxidase
CO is a modulator of ion channels with both excitory and inhibitory effects on numerous classes of ion channels such as voltage-gated calcium channels.
Distribution
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 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 CO to cells and tissues.