Current Medicinal Chemistry (v.22, #3)
Meet the Editorial Board: by Giorgio Ascoli (291-291).
Cardio-vascular Activity of Catestatin: Interlocking the Puzzle Pieces by R. Mazza, B. Tota, A. Gattuso (292-304).
Catestatin (CST), the Chromogranin A (CgA)-derived cationic and hydrophobic peptide, firstly recognized as an endogenous inhibitor of catecholamine secretion, functions as a physiological brake of the adreno-sympathetic-chromaffin system. Its wide spectrum of activities includes relevant multilevel cardiovascular and antihypertensive influences. At central systemic level, CST seems to modulate the autonomic cardiovascular control possibly acting on baroreceptor afferent fibers of the nucleus tractus solitarius. This, as well as clinical and experimental (CgA-KO mice) evidences point to an important role of CST in the determinism and prevention of essential hypertension. At organ level, CST exerts myocardial (negative inotropy and lusitropy) effects and potently vasodilates endothelin-1 (ET-1)-preconstricted coronaries through β2-adrenergic receptor (AR)-Gi/o protein-nitric oxide (NO)-cGMP signalling, while counterbalancing β adrenergic (ISO) stimulation. The contractile myocardial effects have been deeply analysed in fish and amphibian hearts, highlighting finely diversified mechanisms of action. CST also acts as cardioprotective agent in both pre- and post-conditioning through NO-dependent mechanisms implicating the Reperfusion Injury Salvage Kinase (RISK) signalling and the activation of mitoKATP channels. The CST-elicited cardiotropic and coronarotropic influences, along with the recently discovered proangiogenic and regulatory effects in glucose and lipid metabolism, contribute to delineate an integrated and updated picture of the peptide which emerges as a pleiotropic hormone with a wide range of cytokine-like characteristics. The aim of this review is to interlock some older and more recent evidences which may help to better perceive the subtle links and differences among the puzzle pieces that still need to be deciphered.
New Antihypertensive Drugs Under Development by J. Tamargo, J. Duarte, L.M. Ruilope (305-342).
Hypertension is the most common cardiovascular disease and remains the most prevalent risk factor for cardiovascular diseases and a major cause of death worldwide. Despite the large number of antihypertensive drugs available, in the majority of patients blood pressure still remains not optimally controlled and persists at high risk of cardiovascular complications. The limitations of current therapies have stimulated the research and development of new classes of antihypertensive agents, with different mechanisms of action, that provide a better blood pressure control, greater protection against organ damage, better tolerability and more effective prevention of cardiovascular diseases. However, essential hypertension is a multifactorial and multigenic disorder, which means that various mechanisms contribute to a greater or lesser extent to increase BP. Recent advances in the understanding of the multiple and complex cellular signalling pathways that modulate vascular smooth muscle cell contraction and growth involved in the regulation of vascular tone and in hypertension-induced end-organ damage have provided valuable insight in identifying new therapeutic targets. This article reviews new antihypertensive drugs under development, focusing on their mechanisms of action and possible advantages compared with traditional drugs.
Oxidative Stress and Post-Stroke Depression: Possible Therapeutic Role of Polyphenols? by Seyed Fazel Nabavi, Olivia M. Dean, Alyna Turner, Antoni Sureda, Maria Daglia, Seyed Mohammad Nabavi (343-351).
Post-stroke depression is a common neuropsychiatric affective disorder that may develop after a stroke event. In addition to abnormalities in the biogenic amine neurotransmitters and cytokine expression induced by stroke we will focus on the role of oxidative stress and hypothesize that polyphenols may be useful as therapeutics targets for the treatment of post-stroke depression. In this paper, we discuss the hypothesis that increased oxidative stress in cerebral tissues during ischemia is implicated in the pathogenesis of depressive-like symptoms following stroke. There is substantive evidence regarding the role of oxidative stress in the pathogenesis of both stroke and depression, which provides support to this hypothesis. Reactive oxygen species, generated during stroke, cause oxidative stress, lipid peroxidation, protein oxidation, and DNA damage in neural tissues. The resultant pathophysiological processes in the neural tissues could be considered a leading mechanism in the induction of post-stroke depression. Antioxidants including polyphenols therefore, may play an important role in the outcomes of ischemia and stroke, due to their ability to protect neurons against oxidative stress, to mitigate ischemic damage via inhibition of lipid peroxidation and ability to interact with the generation of nitric oxide from the vascular endothelium, and also to decrease inflammation. These data suggest that polyphenols may therefore be a useful new therapeutic target for the treatment of post-stroke depression.
Endless Peptides - Circular Forms in Nature by Anna Adamska, Anna Janecka (352-359).
Nature provides us with an enormous diversity of chemical structures which is an inspiration to chemists and pharmacologists seeking new drug candidates. Circular peptides which have been identified in bacteria, fungi, plants and some mammals but not in humans display exceptional stability and potent bioactivities. They play important roles as defense molecules for their host organisms, providing protection against microorganisms or insects and therefore can be adapted as scaffolds in drug development. Here we try to summarize the most important facts about the origin, biosynthesis and activities of this interesting group of natural products.
Interaction Between DNA/histone Methyltransferases and their Inhibitors by J. Hu, S. Chen, X. Kong, K. Zhu, S. Cheng, M. Zheng, H. Jiang, C. Luo (360-372).
Epigenetic research has recently become one of the hotspots in the field of bioscience and drug design. DNA methylation and histone methylation serve a critical function in influencing gene expression and genome function. The inhibition of DNA and histone methyltransferases (DNMTs and HMTs) is a promising approach for the therapeutic treatment of numerous diseases, including cancer. This work reviews the recent achievements in methyltransferase crystallographic structure resolution and bioactive inhibitor screening. We discuss the features of DNA and HMT structures, as well as the mechanism and structure-function relationship of transferase inhibitors, to elucidate how methyltransferase and inhibitor interactions occur both internally and externally. This study briefly reviews the biological function, as well as the inhibitor discovery and development, of DNA/histone methyltransferases.
Recent Development of Multifunctional Agents as Potential Drug Candidates for the Treatment of Alzheimerµs Disease by Natalia Guzior, Anna Wieckowska, Dawid Panek, Barbara Malawska (373-404).
Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. This review updates information on the development of multifunctional potential anti-AD agents published within the last three years. The majority of the recently reported structures are acetylcholinesterase inhibitors, often endowed with some additional properties. These properties enrich the pharmacological profile of the compounds giving hope for not only symptomatic but also causal treatment of the disease. Among these advantageous properties, the most often reported are an amyloid-β antiaggregation activity, inhibition of β-secretase and monoamine oxidase, an antioxidant and metal chelating activity, NOreleasing ability and interaction with cannabinoid, NMDA or histamine H3 receptors. The majority of novel molecules possess heterodimeric structures, able to interact with multiple targets by combining different pharmacophores, original or derived from natural products or existing therapeutics (tacrine, donepezil, galantamine, memantine). Among the described compounds, several seem to be promising drug candidates, while others may serve as a valuable inspiration in the search for new effective therapies for AD.