Current Enzyme Inhibition - Volume 4, Issue 3, 2008

The discoveries of the pluripotent role of glycogen synthase kinase-3 (GSK-3) are pointing to GSK-3 as a potential target for therapy of neurodegenerative disorders and type 2 diabetes. GSK-3 is a constitutively active protein kinase that is inhibited in response to various extracellular signals. Lithium has been found to be an important inhibitor of GSK-3 activity and its use as a laboratory tool has contributed to the understanding of the role of GSK-3. Fluoride has been often used in study designs on GSK-3 as the inhibitor of protein phosphatases. Potential interactions of fluoride with the observed lithium effects are discussed.

Liver steatosis, or fatty liver, is characterized by the excess accumulation of triglycerides and fatty acids within hepatocytes. This accumulation is marked by an imbalance between the import/synthesis and export/degradation of fat in the liver. Liver steatosis is typically a benign condition, but is associated with severe complications following major liver surgery, as well as the progression of the liver to fibrosis, cirrhosis, and hepatocellular carcinoma. The hallmark of treatment has traditionally been the use of behavioral modification leading to long-term phenotypic reversal. However, the rapid reversal of liver steatosis is essential, especially prior to surgeries including hepatic resection or transplantation. The liver is a primary lipogenic tissue, making the enzyme fatty acid synthase (FAS, EC 2.3.1.85) a logical target for the treatment of steatosis. For steatosis of alcoholic or nonalcoholic etiology, fat accumulation is linked to the de novo synthesis of fatty acids through FAS. Recent reports have shown success using FAS inhibitors to reduce the amount of liver steatosis, and to reduce ischemia/reperfusion injury in those livers. Thus, FAS emerges as a key target for the reversal of hepatic steatosis, both for the preconditioning of livers prior to surgery.

Ezetimibe is the first lipid-lowering drug which selectively inhibits the intestinal uptake of dietary and biliary cholesterol by binding to the cholesterol transporter protein Niemann-Pick C1 Like 1 (NPC1L1). This drug is an effective new tool for cholesterol lowering and allows to better investigate the mechanisms involved in cholesterol absorption by small intestine. Ezetimibe is rapidly absorbed after oral administration and extensively metabolized (>80%) to the pharmacologically active ezetimibe-glucuronide compound; furthermore, it shows a favourable drug-drug interaction profile due to the absence of clinically relevant interactions with a variety of drugs commonly used in patients with hypercholesterolemia (in particular, statins, fibrates and nicotinic acid). In primary hypercholesterolemia, ezetimibe alone reduces low density lipoprotein (LDL) cholesterol by about 18% and induces an additional 25% reduction when added to on-going statins. The combination therapy of ezetimibe with statins or fibrates is effective and safe also in patients affected by the Metabolic Syndrome, which is characterized by complex lipid alterations, including increased triglyceride levels, low high density lipoprotein (HDL) cholesterol concentrations, preponderance of small dense LDL particles and post-prandial hyperlipidemia. In this review, we considered the main studies evaluating the rationale and the efficacy of therapy with ezetimibe alone or in combination with other lipid-lowering drugs, in order to provide clinical indications.

Enzyme inhibition is a fundamental process to preserve the orderly sequence of events required for life, from seed germination to apoptosis. This review will verse on recent findings showing the various ways in which enzyme inhibition has been incorporated into the arsenal of many organisms, either as an effective defensive weapon or as a factor needed for the establishment of infection, parasitism and/or symbiotic associations, and how this diverse functionality can be exploited for therapeutic uses. It will describe several non-proteinaceous enzyme inhibitors isolated from natural sources or synthesized on the basis of structural or functional similarity to biosynthetic enzymes that have been employed for effective treatment against infections and/or aggresive diseases, such as cancer and AIDS, given their ability to disrupt critical functions of the target organisms or malignant cells. A relation of novel plant proteinase inhibitors (PPIs) with multiple and/or novel functions or engineered to have a highly selectivity on their target enzymes in order to avoid deleterious effects in a multi-trophic level that negatively affect insect pollinators or predators, is included too. This development could eliminate or reduce one of the most pressing concerns about the use of PIs as transgenes in many important crops. Finally, an account of the highly specific inhibition of enzymatic activity by biotechnological (e.g. gene silencing) or biochemical means, which have proven to be powerful tools to reveal novel functions for a variety of enzymes will be made in the context of defense, development, senescence and programmed cell death in plants.

The chromosome passenger complex (CPC) is composed of five proteins: Aurora B kinase, Borealin, INCENP, Survivin and TD-60. CPC functions as an oligo-enzyme, each member activating the catalytic subunit, Aurora B kinase. CPC controls chromosome congression, bidirectional tension on kinetochores and spindle checkpoint signalling as well as cytokinesis completion. CPC is thus a key regulator during mitosis; CPC proteins are exclusively expressed during mitosis and are up-regulated in many tumours. Their overexpression correlates with the level of genomic instability within tumours. Altogether, this leads to the proposal of passenger proteins as potential targets for cancer therapy. This review describes the chromosomal passenger complex and its involvement in mitosis and the different strategies developed towards its inactivation.