CORM-3 Reactivity Towards Proteins: The Crystal Structure of a Ru(II) Dicarbonyl-Lysozyme Complex
Teresa Santos-Silva
REQUINTE-CQFB, Departamento de Química, FCT-UNL, 2829-516 Caparica, Portugal
Abstract:
The aim of this drug design project, in collaboration with the Portuguese Pharmaceutical company ALFAMA is to study, at the molecular level, the interaction of potential drugs involved on the prevention and treatment of inflammatory or inflammation-related diseases with plasma proteins. These diseases account for major morbidity and mortality in developed countries. The compounds under study are named CORM, (CO Releasing Molecules), and are responsible for carbon monoxide (CO) delivery in the cells. CORM-3, [fac-Ru(CO)3Cl(κ2-H2NCH2CO2)], is a metalloorganic complex capable of delivering CO in vivo. The interaction of CORM-3 with proteins, namely, hen egg white lysozyme, has been performed by several techniques such as Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES), Liquid-Chromatography Mass Spectrometry (LC-MS), Infrared Spectroscopy (IR) and X-ray crystallography. It was observed that the interactions of CORM-3 with proteins resulted in the loss of a chloride ion, glycinate and one CO ligand. The rapid formation of stable adducts between the protein and the remaining cis-RuII(CO)2 fragments was observed. The structure of hen egg white lysozyme crystals soaked with CORM-3 shows three different coordination sites. The site with highest Ru occupancy (85%) shows a fac-[(His15)Ru(CO)2(H2O)3] structure.
Teresa Santos-Silva, Abhik Mukhopadhyay, João D. Seixas, Gonçalo J. L. Bernardes, Carlos C. Romão, and Maria J. Romão, JACS, accepted.
Keywords: drug design, protein, CORM-3, LC-MS, ICP-AES
