Carbon monoxide guided shuttles (COGSs) to fight Rheumatoid Arthritis - FCT

In the past decade, it has been established that CO behaves as a regulatory molecule at pathophysiological concentrations providing therapeutic effects in many cellular and biological processes even when applied exogenously. CO is a signalling molecule or gasotransmitter, which, together with NO and H2S, has crucial cytoprotective roles in living organisms. The therapeutic potential of such cytoprotective actions, has been demonstrated in animal models of vascular diseases, inflammatory diseases, transplantation and a host of other indications. However, the translation of this potential into real, practical CO based therapy faces many hurdles and is still unrealised. The natural ability of hemoglobin to scavenge CO precludes the use of CO inhalation as a useful form of treatment. Although used in animal models and human clinical trials such method lacks tissue specificity and requires the use of high CO concentrations in systemic circulation to produce biological effects. Such problems should be circumvented by prodrugs that survive in circulation and are designed to target the organ in need where they will release CO in response to some locally expressed trigger. This project focuses on the design, preparation and study of a new type of such prodrugs, named CO Guided Shuttles (COGS) that are capable of transporting and delivering CO to joints for the treatment of Rheumatoid Arthritis. So far, all CO Releasing Molecules (CORMs) are transition metal carbonyl complexes, M(CO)xLy. The earlier ones were quite labile molecules decomposing in biological media and plasma. In most cases they released CO gas in the blood, thereby mimicking inhalation. Exceptionally, the {Ru(CO)3}2+ derivatives, produced biological effects without releasing CO to the blood but lacked organ specificity and plasma stability. On the contrary, sophisticated CORMs with drug-like ADMET profiles were made by CCRomao but are very difficult and time consuming to design and test. A new approach to stable, targeted CO delivery molecular species emerged from a recent seminal discovery of the group of the PI: the interaction of the {Ru(CO)3}2+ based CORMs with proteins originates {Ru(CO)x}2+ protein adducts. These are largely stable in blood and are capable to deliver CO to cells. This finding opens the possibility to transport and deliver CO from biological molecules capitalising on the added value of their molecular recognition abilities for targeting. Our goal is to create target specific CO agents.