SWEET-CO

Carbon monoxide (CO), which is produced in tissues by the inducible defensive protein heme oxygenase-1 (HO-1), is a known anti-inflammatory and cytoprotective gas mediator. Our group has pioneered the discovery of CO-releasing molecules (CO-RMs) to deliver controlled amounts of CO to biological systems and confirmed their therapeutic applicability in vascular, ischemic and inflammatory diseases. We have recently published that CO-RMs act as mild uncouplers of mitochondrial respiration in different cell types. In this context, our data just accepted for publication show that oral administration of a manganese-based CO carrier (CORM-401) stimulates weight loss and counteracts the impairment of metabolism in obese mice via a mechanism that involves mitochondrial uncoupling in adipose tissues. This effect is reminiscent of that exerted by uncoupling agents known to induce weight loss. Because the delivery of CO in vivo is not specific, we aim to synthesize and evaluate novel molecules that direct CO specifically to adipocytes in order to maximize the efficacy of CO-RMs. To achieve this, we propose a strategy to develop CO-RMs conjugated to bioactive polysaccharides known to enhance the delivery of drugs to adipose tissue. We will refer to these new chemical entities as ‘glyco-CORMs’. Building on our preliminary findings, the main OBJECTIVES of this proposal are: 1) to synthesize glyco-CORMs by conjugating CORM-401 homologs with bioactive sugars for targeted delivery of CO to adipose tissue; 2) to characterize in vitro the biological activities of glyco-CORMs by focusing on their effects in adipocytes metabolism and inflammation; 3) to assess in vitro and in vivo the ability of glyco-CORMs to preferentially target adipose cells and tissues; 4) to evaluate the efficacy of glyco-CORMs to reduce metabolic dysfunction in obese mice. The successful accomplishment of this project will rely on the expertise and synergistic collaboration between biologists with a strong background on the pharmacological effects of CO/CO-RMs in metabolism (Dr Foresti-Coordinator-Partner 1), organic chemists having acquired experience in the synthesis of hybrid CO-RMs (Dr Rivard-Partner 2) and an industrial partner (CarboMimetics) with long-standing experience on sugar chemistry and drug discovery (Dr El Hadri-Partner 3). The synthesis of glyco-CORMs is an achievable goal because Dr Foresti and Dr Rivard have established a long-standing collaboration based on the successful synthesis of CO-RMs hybridized to bioactive molecules that are being investigated as anti-inflammatory agents. The consortium will apply state-of the art techniques developed to study the biological role of CO in cell metabolism (Seahorse Analyzer) and to evaluate its preferential accumulation in adipose tissue in vivo. Moreover, for future translational applications, we are partnering with CarboMimetics, a company dedicated to the discovery and development of fully synthetic active saccharide fragments that exert therapeutic action in diabetes and can be conjugated to CO-RMs. Although CO-RMs have undisputed pharmacological effects, we expect that glyco-CORMs will act specifically on adipose tissue, creating new chemical entities to be applied within the defined clinical indication of obesity and metabolic derangement.