Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 15, Number 19, 2008

Contents


Therapeutic Targets in Prostaglandin E₂ Signaling for Neurologic Disease Pp. 1863-1869
P.J. Cimino, C. Dirk Keene, Richard M. Breyer, Kathleen S. Montine and Thomas J. Montine
[Abstract] [Purchase Article]


Protein Kinase CK2 in Human Diseases Pp. 1870-1886
Barbara Guerra and Olaf-Georg Issinger
[Abstract] [Purchase Article]


Trans-Resveratrol: A Magical Elixir of Eternal Youth? Pp. 1887-1898
Francisco Orallo
[Abstract] [Purchase Article]


Myelin Sheaths and Autoimmune Response Induced by Myelin Proteins and Alphaviruses. I. Physicochemical Background Pp. 1899-1910
Jan Sedzik
[Abstract] [Purchase Article]


Pharmacotherapy of Acute Lung Injury and Acute Respiratory Distress Syndrome Pp. 1911-1924
Krishnan Raghavendran, Gloria S. Pryhuber, Patricia R. Chess, Bruce A. Davidson, Paul R. Knight and Robert H. Notter
[Abstract] [Purchase Article]


Therapeutic Drug Monitoring in the Management of HIV-Infected Patients Pp. 1925-1939
Ivanovic Jelena, Nicastri Emanuele, Ascenzi Paolo, Bellagamba Rita, De Marinis Elisabetta, Notari Stefania, Pucillo Leopoldo Paolo, Tozzi Valerio, Ippolito Giuseppe and Narciso Pasquale
[Abstract] [Purchase Article]


Chemical and Genetic Engineering Strategies to Improve the Potency of Pharmaceutical Proteins and Enzymes Pp. 1940-1955
Dimitris Platis and Nikolaos E. Labrou
[Abstract] [Purchase Article]


New Anti-Tuberculosis Drugs with Novel Mechanisms of Action Pp. 1956-1967
Emma C. Rivers and Ricardo L. Mancera
[Abstract] [Purchase Article]




Abstracts


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Therapeutic Targets in Prostaglandin E₂ Signaling for Neurologic Disease
P.J. Cimino, C. Dirk Keene, Richard M. Breyer, Kathleen S. Montine and Thomas J. Montine

Prostaglandins (PGs) are potent autocrine and paracrine oxygenated lipid molecules that contribute appreciably to physiologic and pathophysiologic responses in almost all organs, including brain. Emerging data indicate that the PGs, and more specifically PGE₂, play a central role in brain diseases including ischemic injury and several neurodegenerative diseases. Given concerns over the potential toxicity from protracted use of cyclooxygenase inhibitors in the elderly, attention is now focused on blocking PGE₂ signaling that is mediated by interactions with four distinct G protein-coupled receptors, EP1-4, which are differentially expressed on neuronal and glial cells throughout the central nervous system. EP1 activation has been shown to mediate Ca²⁺ -dependent neurotoxicity in ischemic injury. EP2 activation has been shown to mediate microglial-induced paracrine neurotoxicity as well as suppress microglia internalization of aggregated neurotoxic peptides. Animal models support the potential efficacy of targeting specific EP receptor subtypes in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and ischemic stroke. However promising these preclinical studies are, they have yet to be followed by clinical trials targeting any EP receptor in neurologic diseases.


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Protein Kinase CK2 in Human Diseases
Barbara Guerra and Olaf-Georg Issinger

Protein kinase CK2 (formerly referred to as casein kinase II) is an evolutionary conserved, ubiquitous protein kinase. There are two paralog catalytic subunits, i.e. alpha (A1) and alpha’ (A2).

The alpha and alpha’ subunits are linked to two beta subunits to produce a heterotetrameric structure.

The catalytic alpha subunits are distantly related to the CMGC subfamily of kinases, such as the Cdk kinases. There are some peculiarities associated with protein kinase CK2, which are not found with most other protein kinases: (i) the enzyme is constitutively active, (ii) it can use ATP and GTP and (iii) it is found elevated in most tumors investigated and rapidly proliferating tissues. With the elucidation of the structure of the catalytic subunit, it was possible to explain why the enzyme is constitutively active [1] and why it can bind GTP [2].

Considerable information on the potential roles of CK2 in various disease processes including cancer has been gained in recent years, and the present review may help to further elucidate its aberrant role in many disease states. Its peculiar structural features [3-9] may be advantageous in designing tailor-made compounds with the possibility to specifically target this protein kinase [10].

Since not all the aspects of what has been published on CK2 can be covered in this review, we would like to recommend the following reviews; (i) for general information on CK2 [11-18] and (ii) with a focus on aberrant CK2 [19-22].


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Trans-Resveratrol: A Magical Elixir of Eternal Youth?
Francisco Orallo

Trans-resveratrol or (E)-resveratrol [3,4',5 trihydroxy-trans-stilbene, t RESV or (E)-RESV] is a natural component of Vitis vinifera L. (Vitaceae), abundant in the skin of grapes (but not in the flesh) and in the leaf epidermis and present in wines (especially red wines). In in vitro, ex vivo and in vivo experiments, t-RESV exhibits a number of biological activities, including anti inflammatory, antioxidant, platelet antiaggregatory and anticarcinogenic properties, and modulation of lipoprotein metabolism. Some of these activities have been implicated in the cardiovascular protective effects attributed to t-RESV and to red wine.

Prior to 2002 there had been no previous studies describing the potential effects of t RESV on the lifespan extension. However, in the last 5 years, several researchers have reported that t RESV is a potent activator of sirtuin enzymatic activity, mimics the beneficial effects of caloric restriction (CR), retards the aging process and increases longevity in a number of organisms from different phyla such as yeasts, worms, flies and short-lived fish. In addition, t-RESV seems to be effective in delaying the onset of a variety of age-related diseases in mammals (e.g.: rodents).

Therefore, this review will basically focus on the possible role of t-RESV to extend life duration and on some of the mechanisms by which t-RESV may act as an anti-aging agent.


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Myelin Sheaths and Autoimmune Response Induced by Myelin Proteins and Alphaviruses. I. Physicochemical Background
Jan Sedzik

Myelin proteins of the central and peripheral nervous system range from very hydrophilic to extremely hydrophobic proteins. Their biological function and involvement in various clinically defined neurological diseases are well documented. In this review the myelin proteins will be compared with proteins of alphaviruses with emphasis on Semliki Forest Virus (strain pSP6-SFV4), to elucidate better the multiple function and the potential role in several neurological diseases.

The main purpose of this review is to assist neuroscientists, neurochemists, neurologists, and other interested scientists in developing a better understanding on the information relating to myelin proteins referred in autoimmune diseases. Therefore, this review is focused on simple physiochemical background of proteins and structural aspect, which may be involved in autoimmunity. It is very unusual that few different a.a. sequences (epitops) induce indeed the same autoimmune reaction.


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Pharmacotherapy of Acute Lung Injury and Acute Respiratory Distress Syndrome
Krishnan Raghavendran, Gloria S. Pryhuber, Patricia R. Chess, Bruce A. Davidson, Paul R. Knight and Robert H. Notter

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapidonset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article.


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Therapeutic Drug Monitoring in the Management of HIV-Infected Patients
Ivanovic Jelena, Nicastri Emanuele, Ascenzi Paolo, Bellagamba Rita, De Marinis Elisabetta, Notari Stefania, Pucillo Leopoldo Paolo, Tozzi Valerio, Ippolito Giuseppe and Narciso Pasquale

The rate of HIV-positive patients that fails to reach or to maintain a durable virological suppression under anti-retroviral (ARV) therapy might be as high as 50%, therefore new tools to improve ARV drug efficacy are urgently needed. Among others, therapeutic drug monitoring (TDM) is a strategy by which the dosing regimen for a patient is guided by measurement of plasma drug levels, enabling physicians to optimize ARV drug efficacy and to avoid drug-related toxicity. The most used analytical methods to determine plasma levels of ARV drugs are HPLC-UV and HPLC-MS(/MS), recently MALDI-based methods and enzyme immunoassay (EIA) technologies have been also employed. The wide inter-patient variability in ARV drug pharmacokinetic supports the application of TDM to the clinical management of HIV-infected patients. Drug-drug and drug-food interactions, drug binding to plasma proteins, drug sequestering by erythrocytes, hepatic impairment, sex, age, pregnancy, and host genetic factors are sources of inter-patient variability affecting ARV drug pharmacokinetics. Combining the information of TDM and resistance tests in genotypic inhibitory quotient (GIQ) is likely to be of great clinical utility. Indeed, only two clinical trials on GIQ, both conducted using ARV drugs not more commonly in use, have shown clinical benefits. The design of new trials with long follow-up and sample size representative of the current HIV prevalence is urgently needed to give indications for GIQ as an early predictor of virological response. Here, the basic principles and the available methods for TDM in the management of HIV-infected patients are reviewed.


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Chemical and Genetic Engineering Strategies to Improve the Potency of Pharmaceutical Proteins and Enzymes
Dimitris Platis and Nikolaos E. Labrou

Over the last decade there has been significant progress in understanding the molecular basis of disease processes. At the same time the technological advances in the area of genomics and the efforts in proteomics research have increased the possibility of discovering many proteins with defined therapeutic functions. A large number of these proteins have found clinical application. Despite the importance of proteins as therapeutic agents, they have a number of disadvantages in comparison to small-molecule drugs, including immunogenicity and antigenicity, poor efficacy and oral bioavailability as well as, in many cases, short serum half-lives. To date, the most promising approaches for improving protein therapeutics rely on the use of genetic engineering and site-specific chemical synthesis/modification techniques. Improving the potency of protein drugs by employing modern recombinant DNA technologies and novel chemical synthesis techniques is of primary importance, not only because of the enormous medicinal benefit but also because of the significant economic edge an improved drug can provide in today’s competitive market.


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New Anti-Tuberculosis Drugs with Novel Mechanisms of Action
Emma C. Rivers and Ricardo L. Mancera

It is estimated that a third of the world’s population is currently infected with tuberculosis, leading to 1.6 million deaths annually. The current drug regimen is 40 years old and takes 6-9 months to administer. In addition, the emergence of drug resistant strains and HIV co-infection mean that there is an urgent need for new anti-tuberculosis drugs. The twenty-first century has seen a revival in research and development activity in this area, with several new drug candidates entering clinical trials. This review considers new potential first-line anti-tuberculosis drug candidates, in particular those with novel mechanisms of action, as these are most likely to prove effective against resistant strains. A brief overview of current first-line and recent drugs (such as fluoroquinolones, rifampicin and isoniazid analogues) is initially presented. This is followed by a description of structure-activity relationships, in vitro and in vivo activity, pharmacokinetics, mechanism of action, combination regimens and clinical trials of the new drug candidates SQ109, PA-824, OPC-67683, TMC207 and others.