REACTIVE CARBONYL SPECIES AS POTENTIAL DRUG TARGETS IN PREVENTING PROTEIN CARBONYLATION AND RELATED CELLULAR DYSFUNCTION

Protein carbonylation induced by reactive carbonyl species (RCS) generated by peroxidation of polyunsaturated fatty acids plays a significant role in the etiology and/or progression of several human diseases, such as cardiovascular (e.g., atherosclerosis, long-term complications of diabetes) and neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and cerebral ischemia)(1). Most of the biological effects of intermediate RCS, mainly alpha,beta-unsaturated aldehydes, di-aldehydes, and keto-aldehydes, are due to their capacity to react with the nucleophilic sites of proteins, forming advanced lipoxidation end-products (ALEs). Because of the emerging deleterious role of RCS/protein adducts in several human diseases, different potential therapeutic strategies have been developed in the last few years. The talk will focus on the fundamental studies on lipid-derived RCS generation, their biological effects, and their reactivity with proteins, with particular emphasis to 4-hydroxy-trans-2-nonenal (HNE)-, acrolein (ACR)-, malondialdehyde (MDA)-, and glyoxal (GO)-modified proteins (2). It will also consider the recently developed pharmacological approaches for the management of chronic diseases in which oxidative stress and RCS formation are massively involved. The most promising strategy to neutralize/reduce these pathogenetic factors is based on nucleophilic compounds capable to form covalent and unreactive adducts with RCS (RCS sequestering agents) such as pyridoxamine (PYR), hydralazine (HY), dihydralazine (di-HY), aminoguanidine (AG), and metformin (MF)(2). However these compounds are characterized by a severe aspecificty since they react also with physiological aldehydes such as pyridoxal (3). The talk will also describe a new class of RCS-sequestering agents developed in our laboratory, derived form the endogenous peptide Carnosine (β-alanyl-L-hisitidine), characterized by a significant quenching activity towards electrophilic aldehydes, and high selectivity. The efficacy of this new class of compounds in preventing dyslipidemia, hypertension and kidney damage in Zucker obese rats will be also presented.