Carbon dioxide (CO) otherwise known as a silent killer is an odorless and colorless gas. The toxicity of CO is due to its high affinity for hemoglobin and other heme molecules, it competitively displaces oxygen(O2) to form carboxyhemoglobin(COHb). Thus, greatly interfering oxygen delivery throughout the body, and metabolically active areas, like heart and brain.
Did you know? If the concentration of carboxyhemoglobin exceeds 50%, it might cause coma, convulsions, depressed respiration and cardiovascular distress or even fatal consequences. Although CO gas is toxic in large doses, scientists have discovered it can have beneficial effects in modulation of diverse physiological and pathological processes, similar to nitric oxide (NO) and hydrogen sulfide (H2S). CO is a stable inert gaseous molecule that freely diffuses into all the cells. At optimal concentrations, CO has been proven to treat many diseases and organ injury.
Some biologically useful properties of CO
• In case of cancer treatment CO is used because it interferes with cytochrome c oxidase in the mitochondria, thus blocking oxidative phosphorylation, in turn interfering with cell growth and proliferation.
• Gaseous CO is not metabolized and reversibly binds to cellular targets, thus making pharmacokinetic and pharmacodynamic studies simpler.
• CO increases mitochondrial biogenesis increasing ATP and ROS generation that influences cellular behaviour.
• CO acts as an antiapoptotic in endothelial cells, hepatocytes and cardiomyocytes, preventing cell and tissue injury.
• It has antiinflammatory properties.
• It is used in organ transplantation.
Carbon monoxide (CO) is being accepted as a cytoprotective and homeostatic molecule with important signalling capabilities in physiological and pathophysiological situations. The advantage of using CO as a therapeutic agent in the biological system is it can preferentially and reversibly bind to transition metals with specific redox states, unlike NO and H2S, which interact indiscriminately with several intracellular targets. The organ protective effects of CO have been demonstrated in injury models of the kidneys, lungs, the gastrointestinal tract, and the liver. It is difficult to deliver a gaseous therapeutic to a patient, and CO being a gas poses a great risk to healthcare workers as well as patients in terms of accidental poisoning hence, there is a need of developing alternative delivery forms.
ATLANTA – It the first examples of orally active, organic CO prodrugs developed by a team of scientists led by Binghe Wang, Regents’ Professor of Chemistry at Georgia State University, delivers carbon monoxide to protect against acute kidney injury. This prodrug allows oral administration of CO using two common artificial sweeteners - saccharine and acesulfame as “carrier” molecules. They designed the molecules to release CO in the process of decomposition, which is triggered by exposure to water. It is approved by the Food & Drug Administration with a demonstrated safety profile. Both the molecules are FDA-approved, non-calorific sweeteners, having pKa values within the range of 1.6 and 3.0, respectively. The research progressed by developing CO prodrugs. The prodrugs were named BW-CO-306 and BW-CO-307, which were made by reaction between commercially available sweeteners saccharin and acesulfame, respectively, with oxalyl chloride in the presence of triethylamine. The release of CO from the prodrug relies on series of steps based on hydrolysis, decarboxylation, decarbonylation reaction sequences.
Image- Structures of CO prodrugs.
In vitro anti-inflammation assays and in vivo pharmacokinetics and acute kidney injury mouse model studies validate the use of this prodrug system to deliver CO for therapeutic applications. Of the two prodrugs, the scientists tested BW-CO-306, for pharmacological efficacy against acute kidney damage. The researchers administered BW-CO-306, which uses saccharine as a carrier molecule, to mice and found it reduced biomarkers associated with kidney injury, indicating it could be developed into a viable therapy. The mouse model was made to mimik the mechanisms of kidney tissue damage that occur in patients with extensive muscle damage, sickle cell disease, a common type of malaria, cardiopulmonary bypass surgery and severe sepsis. It is expected that the prodrug will be put through more extensive animal model studies and safety assessments before progressing to human clinical studies.
Reference:
• Artificial Sweeteners Enable Delivery of Carbon Monoxide to Treat Organ Injury | News Hub | Access date: 22nd July, 2021
• Binghe Wang, et al., Adapting decarbonylation chemistry for the development of prodrugs capable of in vivo delivery of carbon monoxide utilizing sweeteners as carrier molecules. DOI: 10.1039/D1SC02711E (Edge Article) Chem. Sci., 2021, Advance Article. First published on 1st July 2021. [https://pubs.rsc.org/en/content/articlehtml/2021/sc/d1sc02711e]
• Zhou Y, Yu W, Cao J, Gao H. Harnessing carbon monoxide-releasing platforms for cancer therapy. Biomaterials. 2020 Oct;255:120193. doi: 10.1016/j.biomaterials.2020.120193. Epub 2020 Jun 15. PMID: 32569866. Pubmed
• Motterlini R, Otterbein LE. The therapeutic potential of carbon monoxide. Nat Rev Drug Discov. 2010 Sep;9(9):728-43. doi: 10.1038/nrd3228. PMID: 20811383. Pubmed
Content by Manali Somanna
Comments