Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents - Volume 1, Issue 2, 2001

A multitude of regulatory peptides derive from the main members of the granin family, i.e. the chromogranins A (CGA) and B (CGB) and secretogranin II. These proteins are co-secreted from the diffuse neuroendocrine system with a wide range of neurotransmitters and peptide hormones upon adequate stimuli. The recent developments provide ample evidence of widely different effects and targets for the CGA derived peptides, implicated in the regulation of plasma calcium, plasma glucose, adrenomedullary catecholamine release and vascular contractility, as well as in the innate immunity. This review aims to attract the attention of endocrinologists and immunologists to this novel family of regulatory peptides, notably those derived from CGA.The main emphasis has been placed on functional aspects of the precursor protein and the biologically active peptides, such as the vasostatins I and II, pancreastatin and catestatin. The majority of properties so far assigned to this calcium binding prohormone and its peptide derivatives fits into patterns of inhibitory effects, of postulated relevance not only for homeostatic processes, but also in the inflammatory response and the early defence against invading microorganisms.

Acyl-CoA: cholesterol acyltransferase (ACAT) catalyzes the intracellular esterification of free cholesterol (FC) to cholesteryl ester (CE). Two subtypes of ACAT enzymes (ACAT1 and ACAT2) play important roles in lipoprotein assembly from the intestine and liver and intracellular CE accumulation in foam cell formation within vessel walls. Since hypercholesterolemia and foam cell formation are integral to the development of atherosclerosis, many ACAT inhibitors with varying activities against ACAT1 and 2 have been designed and studied for their effects on atherosclerosis. Indeed, these inhibitors lower cholesterol plasma levels and reduce atherosclerosis in animal models. However, in vitro and in vivo studies have suggested that ACAT inhibition could be adrenal toxic in animals and cytotoxic to rodent macrophage foam cells. Cytotoxicity has been linked to excess accumulation of intracellular FC content. In addition, double knockout mice with congenital hyperlipidemia and ACAT1 deficiency have increased extracellular accumulation of FC. These results contrast with in vitro studies examining the effects of ACAT inhibitors on cultured primary human macrophage foam cells. In addition, human subjects treated with ACAT inhibitors appear to tolerate the compound and have not shown signs of toxicity. This review addresses the toxicity concerns of ACAT inhibition and compares and contrasts the in vitro and in vivo studies of ACAT inhibition between experimental animal and human models.

Neuropeptides are molecules of outstanding importance in the regulation of most different physiological and biochemical processes. They act as signal transducting molecules that makes them an ideal target for pharmacological treatment. Because of their possibility to act via different receptor subtypes within a whole receptor family, the peptides are able to selectively induce physiological processes. Therefore, peptide research provides important contributions to a detailed understanding of physiological processes. The hypothalamic regulation of food intake reveals a redundant system of neuropeptides, acting and interacting with each other in order to control energy homeostasis and body weight. Leptin and insulin are peripheral adiposity signals, inducing first order neuronal signalling in the arcuate nucleus of the hypothalamus. There, they inhibit anabolic peptides, whereas they stimulate catabolic peptides. Neurons from the arcuate nucleus project to candidate second-order neurons involved in hypothalamic response to leptin and insulin, located in the paraventricular nucleus and the lateral hypothalamic and perifornical area. However, anomalies in body weight, especially overweight and obesity, are not only genetically determined, but also by the environment. Cultural, socioeconomic and psychosocial factors, physical activity and other environmental factors are known for sustained influence of body weight. Medicinal chemistry importantly contributes to the molecular understanding of anomalies and diseases, which likely culminates in the development of appropriate medical treatments. Hereby, the development of receptor subtype selective agonists and antagonists is a key step. This is exemplified on a set of hypothalamic neuropeptides which are involved in the regulation of food intake.

Scrapie is a slowly developing neurodegenerative disease occurring naturally in sheep and goats. The spectacular crisis involving TSE infection of cattle in the United Kingdom, has been followed by a chain of published speculations linking sheep Scrapie to bovine TSE (BSE or mad cow disease), and finally there are suggestions of a link between BSE and human new variant Creutzfeldt-Jakob disease (nvCJD). Although the number of people ultimately affected by the health effects of nvCJD cannot be predicted, the economic repercussions have been enormous. The TSE agents can be contaminants of products derived from blood and have been inadvertently added to animal food. Although such blood-borne or food-borne TSE agents have been proposed to be of immediate concern for human health following the United Kingdom BSE epidemic, a great deal of basic research on TSE pathophysiology remains to be conducted.Neurotoxicants are generally considered to be exogenous factors that affect normal metabolism of the central nervous system. However, certain naturally occurring substances such as free radicals, steroids, excitatory amino acids, cytokines, and amyloids may be toxic to the central nervous system, and therefore can be considered as endogenous neurotoxicants. Since these endogenous neurotoxicants may accumulate in the brain due to the disruption of the normal protein metabolic processes, they are of considerable interest to the public health community. In this review we will emphasize that prion protein, as a special metabolic agent, causes changes in immune and endocrine systems, which are a function of pathology of the nervous system.

Over the last two decades, we have seen intensive drug discovery efforts aimed at developing cancer therapeutics that specifically target the underlying defects in cellular growth regulation. By virtue of their specificity, these gene-targeted therapeutics are anticipated to be more effective and less toxic than the currently used chemotherapeutic agents. Among the oncogenes associated with human cancers, the ras oncogenes stand out as particularly attractive targets for creation of cancer therapeutics. These genes have been implicated in upto 30% of human cancers and are most commonly found in pancreatic cancer, colon cancer, and adenocarcinoma of the lung. The ras proto-oncogene encodes a 21-kd GTP-binding protein Ras, which is critical in cellular signal transduction associated with cell proliferation. To function in this signal transduction process, Ras must localize to the plasma membrane. A key step in this translocation is the post translational farnesylation of the cysteine residue near the carboxyl-terminal of Ras that is effected by the enzyme, farnesyl protein transferase. Inhibition of Ras farnesylation is therefore a promising approach for developing mechanism-based anticancer drugs.