Carbon monoxide for therapy

“Our remedies oft in ourselves do lie” (William Shakespeare, All’s Well that Ends Well, 1603)

The research work of ALFAMA is focused on the prevention and treatment of inflammatory or inflammation-related diseases. These diseases account for major morbidity and mortality in developed countries. The aim of ALFAMA´s main project is to deliver a natural mediator of anti-inflammatory effects, carbon monoxide (CO), to sites of inflammation. To this end, ALFAMA is developing novel carbon monoxide releasing molecules (CORMs).

In recent years carbon monoxide (CO) has been recognized as an endogenous mediator that is generated by constitutively expressed (HO-2) and inducible (HO-1) enzymes called heme oxygenases.  The finding that upregulation of HO-1 expression has beneficial effects on a wide variety of pathological conditions has stimulated several new drug therapy approaches based on heme oxygenase inducers, cell permeable heme oxygenase-peptide conjugates, or heme oxygenase gene transduction.

An alternative strategy, based on the fact that several of the beneficial effects of HO-1 are mediated by its product CO, is the direct application of CO in its gaseous form. Indeed, impressive therapeutic effects have been achieved in various animal disease models by inhalation of CO as a gas or by oral application of methylene chloride, a compound that generates CO mainly in the liver upon its metabolism. In both cases CO delivery to therapeutic targets involves CO binding to and dissociation from hemoglobin. Amongst the known, endogenous CO binding molecules, hemoglobin has by far the highest affinity, and so a relatively high loading of hemoglobin with CO is required to deliver a therapeutically effective CO dose to target tissues.

Ideally, therapeutic CO would be primarily delivered to targets in diseased tissues before it diffuses into the blood and eventually into the exhaled air. With the ambitious goal of targeted CO delivery in mind, ALFAMA chemists synthesized a large panel of molecules that generate CO under different conditions. These molecules are referred to as CO releasing molecules, a nomenclature introduced by the CORM pioneers Roberto Motterlini and colleagues at the Northwick Park Institute for Medical Research and the University of Sheffield. ALFAMA´s CORMs fall into two major classes, namely organic molecules and metalloorganic complexes. These two CORM classes are reminiscent of organic nitrates and the metalloorganic compound nitroprusside, which have been in clinical use for many decades. Like CORMs these compounds are prodrugs. They deliver NO, while CORMs deliver CO.

Both CO and NO have similar effects on several target proteins and there is a complex interplay between these two gaseous mediators in many tissues of the human body. Because of its stability, more restricted target range, and much lower toxicity at comparable doses, CO may have advantages over NO as a therapeutic principle.