Towards improved therapeutic CORMs: understanding the reactivity of CORM-3 with proteins

The biological role of carbon monoxide (CO) has completely changed in the last decade. Beyond its widely feared toxicity, CO has revealed a very important biological activity as a signaling molecule with marked protective actions namely against inflammation, apoptosis and endothelial oxidative damage. Its direct use as a therapeutic gas showed significant and consistent positive results but also intrinsic severe limitations. The possibility of replacing the gas by pro-drugs acting as CO-Releasing Molecules (CO-RMs) has clearly been demonstrated with several experimental compounds. Transition metal carbonyls complexes have proven to be the most versatile experimental CO-RMs so far. Presently, the challenge is to equip them with drug-like properties to turn them into useful pharmaceuticals. This requires studying their interactions with biological molecules namely those that control their pharmacokinetic and ADME profiles like the plasma proteins. In this account we analyze these questions and review the existing interactions between Metal Carbonyls and proteins. The recently explored case of CORM-3 is revisited to exemplify the methodologies involved and the importance of the results for the understanding of the mode of action of such pro-drugs.