Carbon monoxide-releasing molecules

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.[1]

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

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.[2]

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.[3] HO-2 and HO-3 are constitutive. Other endogenous sources may include lipid peroxidation,[4]

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.

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 rhenium

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.

ET-CORMs

Enyzme triggered CORMs (ET-CORMs) have been developed to improve selective local delivery of CO. Some ET-CORM prodrugs are activated by esterase enyzmes for site specific liberation of CO. [5]

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 (sodium boranocarbonate), 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.

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.

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.[6] 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.[7][8]

Carboxyhemoglobin infusion

Carboxyhemoglobin can be infused to deliver CO. The most common approaches are based on polyethylene glycol (PEG)-lyated bovine carboxyhemoglobin and maleimide PEG conjugated human carboxyhemoglobin.

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.[9] 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[10] thereby identifying the heme oxygenase (HO) 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.[11] The average carboxyhemoglobin (CO-Hb) level in a non-smoker is between 0.2% and 0.85% CO-Hb (whereas a smoker may have between 4% and 10% CO-Hb),[12] though geographic location, occupation, health and behavior are contributing variables.

Enzymes

Heme oxygenase

Heme oxygenase (HO) is a heme-containing member of the heat shock protein (HSP) 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.[13]

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 (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.[14][15]

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.[16][17]

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.

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.[18] 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 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[19] 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.[20] 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.

Metabolism

CO is considered non-reactive in the body and primarily undergoes pulmonary excretion and less than 10% is oxidized.[21]

References
  1. Motterlini R, Otterbein LE (September 2010). "The therapeutic potential of carbon monoxide". review article. Nature Reviews. Drug Discovery. 9 (9): 728–43. doi:10.1038/nrd3228. PMID 20811383.
  2. Mahan VL (December 2012). "Neuroprotective, neurotherapeutic, and neurometabolic effects of carbon monoxide". review article. Medical Gas Research. 2 (1): 32. doi:10.1186/2045-9912-2-32. PMC 3599315. PMID 23270619.
  3. Ferrándiz ML, Devesa I (2008). "Inducers of heme oxygenase-1". review article. Current Pharmaceutical Design. 14 (5): 473–86. doi:10.2174/138161208783597399. PMID 18289074.
  4. Wilkinson WJ, Kemp PJ (July 2011). "Carbon monoxide: an emerging regulator of ion channels". review article. The Journal of Physiology. 589 (Pt 13): 3055–62. doi:10.1113/jphysiol.2011.206706. PMC 3145923. PMID 21521759.
  5. Different design of enzyme-triggered CO-releasing molecules (ET-CORMs) reveals quantitative differences in biological activities in terms of toxicity and inflammation. Stamellou E, Storz D, Botov S, Ntasis E, Wedel J, Sollazzo S, Krämer BK, van Son W, Seelen M, Schmalz HG, Schmidt A, Hafner M, Yard BA, Redox Biol. 2014 Jun 5;2:739-48. doi: 10.1016/j.redox.2014.06.002. eCollection 2014.
  6. Heinemann SH, Hoshi T, Westerhausen M, Schiller A (April 2014). "Carbon monoxide--physiology, detection and controlled release". review article. Chemical Communications (Cambridge, England). 50 (28): 3644–60. doi:10.1039/c3cc49196j. PMC 4072318. PMID 24556640.
  7. Nguyen D, Boyer C (September 2015). "Macromolecular and inorganic nanomaterials scaffolds for carbon monoxide delivery: recent developments and future trends. ACS Biomaterials Science & Engineering". review article. ACS Biomaterials Science & Engineering. 1 (10): 895–913. doi:10.1021/acsbiomaterials.5b00230.
  8. Kautz AC, Kunz PC, Janiak C (November 2016). "CO-releasing molecule (CORM) conjugate systems". review article. Dalton Transactions (Cambridge, England : 2003). 45 (45): 18045–18063. doi:10.1039/c6dt03515a. PMID 27808304.
  9. Maines MD (July 1988). "Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications". review article. FASEB Journal. 2 (10): 2557–68. doi:10.1096/fasebj.2.10.3290025. PMID 3290025.
  10. Tenhunen R, Marver HS, Schmid R (December 1969). "Microsomal heme oxygenase. Characterization of the enzyme". primary article. The Journal of Biological Chemistry. 244 (23): 6388–94. PMID 4390967.
  11. Wang R, ed. (2001). Carbon monoxide and cardiovascular functions. review article (first ed.). CRC Press. p. 5. ISBN 978-1-4200-4101-9.
  12. Thom SR (2008). "Chapter 15: Carbon monoxide pathophysiology and treatment". In Neuman TS, Thom SR (eds.). Physiology and medicine of hyperbaric oxygen therapy. review article. pp. 321–347. doi:10.1016/B978-1-4160-3406-3.50020-2. ISBN 978-1-4160-3406-3.
  13. Correa-Costa M, Otterbein LE (2014). "Eat to Heal: Natural Inducers of the Heme Oxygenase-1 System.". In Folkerts G, Garssen J (eds.). Pharma-Nutrition. review article. AAPS Advances in the Pharmaceutical Sciences Series. 12. Springer, Cham. pp. 243–256. doi:10.1007/978-3-319-06151-1_12. ISBN 978-3-319-06150-4.
  14. Lundh B, Johansson MB, Mercke C, Cavallin-Stahl E (December 1972). "Enhancement of heme catabolism by caloric restriction in man". primary article. Scandinavian Journal of Clinical and Laboratory Investigation. 30 (4): 421–7. doi:10.3109/00365517209080280. PMID 4639647.
  15. Breman HJ, Wong RJ, Stevenson DK (30 October 2001). "Chapter 15: Sources, Sinks, and Measurement of Carbon Monoxide". In Wang R (ed.). Carbon Monoxide and Cardiovascular Functions. review article (2nd ed.). CRC Press. ISBN 978-0-8493-1041-6.
  16. Wolff DG (December 1976). "The formation of carbon monoxide during peroxidation of microsomal lipids". primary article. Biochemical and Biophysical Research Communications. 73 (4): 850–7. doi:10.1016/0006-291X(76)90199-6. PMID 15625852.
  17. Nishibayashi H, Omma T, Sato R, Estabrook RW, Okunuki K, Kamen MD, Sekuzu I, eds. (1968). Structure and Function of Cytochromes. review article. University Park Press. pp. 658–665.
  18. Kim HP, Ryter SW, Choi AM (2006). "CO as a cellular signaling molecule". review article. Annual Review of Pharmacology and Toxicology. 46: 411–49. doi:10.1146/annurev.pharmtox.46.120604.141053. PMID 16402911.
  19. Correia MA, Ortiz de Montellano PR (2005). "Inhibition of cytochrome P450 enzymes". Cytochrome P450. review article. Boston, MA: Springer. pp. 247–322. doi:10.1007/0-387-27447-2_7. ISBN 978-0-306-48324-0.
  20. Blumenthal I (June 2001). "Carbon monoxide poisoning". review article. Journal of the Royal Society of Medicine. 94 (6): 270–2. doi:10.1177/014107680109400604. PMC 1281520. PMID 11387414.
  21. Wilbur S, Williams M, Williams R, Scinicariello F, Klotzbach JM, Diamond GL, Citra M (2012). "Health Effects". Toxicological Profile for Carbon Monoxide. review article. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry. PMID 23946966.

Further reading
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.