Current Enzyme Inhibition - Volume 2, Issue 3, 2006

Protease inhibitors (PIs) are present in a wide variety of living organisms including microorganisms, plants, and animals. These molecules act as regulators of endogenous proteolytic activity, as participants in many developmental processes and as host's defense components. Because of their important role in living organisms, PIs have been extensively studied in order to allow a better understanding of their structural and functional properties. Intensive works have reported that proteinaceous PIs are potential compounds in several distinct economical and clinical fields. This review aims to describe proteinaceous PIs structure and design, focusing on their multiple potential applications in agriculture; immune system; parasitic, bacterial, fungal, and viral infection; hemostasis; and cancer.

Hypoxic-ischemic brain damage remains an outstanding cause of death and long-lasting disabilities for newborns worldwide. Among the different constituents of the complex cascade of events leading to neuronal death after a hypoxic-ischemic insult in immature brain, nitric oxide (NO) plays a role of great importance. The evidence suggests that NO can exert both protective and deleterious effects depending on factors such as the NOS isoform and the temporal stage after the onset of the ischemic brain injury. Immediately after brain hypoxic-ischemic insult, NO release from eNOS is protective mainly by promoting vasodilation; in this regard, NO is to be of particular relevance for autoregulatory responses of newborn cerebral vessels. However, subsequent NO production by overactivation of nNOS and, later, NO release by de novo expression of iNOS contributes to the brain damage; immature brain is particularly sensitive to this circumstance, as iNOS is more easily and more intensively expressed in newborns after hypoxic-ischemic insults, and newborns have less antioxidant activity, as compared with adults. Thus, NOS emerges as a decisive target for neuroprotection after newborn asphyxia. Toxic effects of drugs specifically acting on NOS, however, still prevent their use in humans. Nevertheless, recent evidences on the unspecific modulatory effect on NOS of substances as erythropoietin or cannabinoids, with few known adverse effects in newborns, offer promising perspectives.

Oxidative stress can result from diminished antioxidant protection as well as increased free radical production. A sophisticated enzymatic [including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)] and non-enzymatic [glutathione, vitamins A, C, and E, and some minerals] antioxidant defense system counteract and regulates overall ROS levels to maintain physiological homeostasis. In addition to this internal antioxidant defense system, it is important to consider the role of exogenous antioxidants from the diet, such as polyphenols and carotenoids, among others bioactive compounds. A great body of evidence tries to elucidate the role of these compounds in the protection of plant-derived foods against degenerative diseases. Thereby, in this review recent studies in cellular, animal and human models will be described, which evaluate the role of polyphenols and carotenoids in the antioxidant defense system against oxidative stress through the modulation of the antioxidant enzymes. Studies reviewed show that the antoxidant enzyme response to normal or oxidative stress situations depends on the enzyme involved, the animal specie or cell line selected, in addition to the features of the intervention or treatment carried out (doses, length, and design of experiments). The most abundant model in these studies has been the animal model due to its ability of being model of induced oxidative stress. In most of the studies when oxidative stress arises, the treatment, supplementation or intervention done prevent or attenuate the decrease in the antioxidant enzyme. Further research is needed to clarify how dietary polyphenols and carotenoids modulate cellular antioxidant enzyme concentrations and how they contribute to regulate the molecular mechanisms and cellular signaling pathways.

Chemistry, pharmacology and applications of compounds inhibiting enzymatic acetylcholine (ACh) degradation are reviewed. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), or non-specific cholinesterase, are members of the family of cholinesterase (ChE), the ACh degrading enzymes. ChE inhibitors (is) are compounds inhibiting reversibly or irreversibly enzymatic ACh breakdown. The first ChE-is were organophosphate derivatives, synthesized as neurotoxic agents. These compounds cause toxic accumulation of ACh at the central and autonomic nervous system level and induce several neurological and autonomic effects including ataxia, seizures, coma, and respiratory depression. This strong toxicity is the reason of their identification as warfare agents. The subsequent main use of ChE-is was as pesticides. ChEs are important enzymes needed for proper functioning of insect nervous system. Although ChE-is are intended for insect pests, in some situations they can be poisonous or toxic to humans. The most recent and promising use of AChE/BuChE-is was symptomatic treatment of cognitive dysfunction occurring in Alzheimer's disease (AD). Forebrain cholinergic system has a key role in learning and memory and AD is characterized by brain cholinergic impairment. AChE/BuChE-is are the first drugs approved for symptomatic treatment of cognitive deficits in AD. Besides cognitive relief induced in mild-to-moderate AD, increasing evidence suggests that ChE-is may interfere with the progression of the disease. If this hypothesis will be supported by ongoing studies, these compounds could become a disease-modifying strategy in the treatment of adult-onset dementia.

Inhibitors of HMG-CoA reductase (statins) are widely used for the treatment of hypercholesterolemia. Besides this very important action, several other effects of statins, contributing to the general benefit of patients with coronary heart disease, have recently been demonstrated. These include: stabilization of atheroma plaques; inhibition of platelet aggregation; anti-inflammatory effects; improvement of vasomotor and endothelial function; antiproliferative effects on vascular smooth muscle cells; and effects on fibrinolytic activity, resulting in a decreased mortality from coronary heart disease, regardless of the influence on the serum cholesterol levels. Other effects of statins involve antioxidative, immunomodulatory and potential anti-tumor activities, as has been suggested by a number of studies either demonstrating the beneficiary activities of statins on the rejection of transplanted organs, or the low prevalence of cancer in patients having received statin medication. The aim of the present survey is to summarize current knowledge in this biomedical field and to demonstrate the enormous curative potential of this group of drugs.

Drug metabolism is a major determinant of drug clearance, interindividual pharmacokinetic differences and, indirectly, of the clinical efficacy and toxicity of drugs. Altered pharmacokinetics can result in inadequate concentration of the drug at the site of action and/or great variations in clinical response. Therefore, the development of a new drug requires not only an exhaustive characterisation of its pharmacological activity, but also knowledge of major enzymes involved in metabolite formation, and the potential enzyme inhibiting or enzyme inducing properties of the drug. Multi-drug therapy is not uncommon in clinical practice. Simultaneous administration of several drugs may result in metabolic drug-drug interactions having pharmacological and/or toxicological implications. As drugs are metabolised by a limited number of enzymes, they can compete each other as substrates for the same enzyme. Thus, competitive/non-competitive/irreversible inhibition of drug-metabolising enzymes by one of the therapeutic agents will result in elevations in plasma/tissue concentrations of the other drugs. For compounds with a narrow therapeutic index, this can lead to overdosage symptoms and/or toxicity. Cytochrome P450 (P450) enzymes are major players in the oxidative metabolism of therapeutic agents and, consequently, the most common mechanism underlying drug-drug interactions is the inhibition of P450 activities. Several drugs in common use cause large increases in exposure to other drugs. As this is an undesirable feature for a drug candidate, information about P450 inhibition by the compound should be obtained before a drug candidate is considered for the clinical stages of development. A combination of biochemical advances in the understanding of the function and regulation of drug-metabolising enzymes, in particular P450s, and automated analytical technologies are revolutionising drug metabolism research.

In the last 12 years, data has accumulated supporting an important role for hyperglycemia in the development of diabetic nephropathy, and in the same period identification and characterization of renal glucose transporters has expanded rapidly. This new knowledge concerning glucose transporters is now being used to determine the roles they may play in diabetic kidney disease. Recent studies of renal glucose transporters have characterized their responses to diabetes, and their potential roles in the diabetic kidney. Glucose transporters have been shown to be rate-limiting for mesangial cell glucose uptake, glucose metabolism and extracellular matrix (ECM) production by these cells. Furthermore, increased renal GLUT1 has been proposed to play an important role in the development of diabetic glomerulosclerosis. Recent data suggest increased GLUT8 in podocytes may contribute to diabetic glomerular disease as well. Renal tubular glucose transporter expression is also altered in diabetes, responding to the increased need for glucose reabsorption . However, further investigation is required to determine the potential roles of these glucose transporters in the interstitial kidney disease associated with diabetes.