Book Volume 5
Page: i-ii (2)
Author: Allen B. Reitz, Atta-ur-Rahman and M. Iqbal Choudhary
Page: vi-ix (2)
Author: Atta-ur-Rahman, Allen B. Reitz and M. Iqbal Choudhary
Always Around, Never the Same: Pathways of Amyloid Beta Induced Neurodegeneration Throughout the Pathogenic Cascade of Alzheimer
Page: 1-14 (14)
Author: Jeroen J.M. Hoozemans, Sidhartha M. Chafekar, Frank Baas, Piet Eikelenboom and Wiep Scheper
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There is an increasing amount of evidence showing the importance of intermediate aggregation species of amyloid β (Aβ) in the pathogenic cascade of Alzheimer's disease (AD). Different Aβ assembly forms may mediate diverse toxic effects at different stages of the disease. Mouse models for AD suggest that intraneuronal accumulation of Aβ oligomers might be involved in AD pathogenesis at a very early stage of the disease. The detrimental effect of oligomeric Aβ on synaptic efficacy is suggested to be an early event in the pathogenic cascade. Also early neuronal responses as activation of the unfolded protein response are processes likely to be associated with the increased occurrence of oligomeric or low fibrillar Aβ in AD pathology. In later stages of AD pathology, the fibrillarity of Aβ increases, concomitantly with a neuroinflammatory response, followed by tau related neurofibrillary changes in end stage pathology. We will review recent findings in in vitro cell models, in vivo mouse models, and post mortem AD brain tissue in view of the effects of different Aβ peptide species on neurodegeneration during AD pathogenesis. Insight into the role of different Aβ species during AD pathogenesis is essential for the development of disease modifying drugs and therapeutical strategies
Novel Neuroprotective Therapies for Alzheimer's and Parkinsons's Disease
Page: 15-57 (43)
Author: Kirubakaran Shanmugam, Annette E.Maczurek, Megan L.Steele, Obdulio Benavente-García, Julian Castillo and Gerald Munch
One of the major age-related damaging agents are reactive oxygen species (ROS). The brain is more vulnerable to oxidative stress than other organs as concomitant low activity and capacity of antioxidative protection systems allow for increased exposure of target molecules to ROS. Since neurons are postmitotic cells, they have to live with cellular damage accumulated over many decades. Increased levels of ROS (also termed “oxidative stress”), produced by normal mitochondrial activity, inflammation and excess glutamate levels, are proposed to accelerate neurodegenerative processes characteristic for Alzheimer's disease and Parkinson's disease. This review presents evidence for the importance of oxidative stress in the pathogenesis of these diseases and explains the nature of different types of ROS mediating neuronal damage. Furthermore, the potential beneficial effects of neuroprotective treatments, including synthetic and plant deroved antioxidants, energy supplements and anti - glutamatergic drugs are discussed.
Improving Memory: A Role for Phosphodiesterases
Page: 58-80 (23)
Author: Arjan Blokland1, Rudy Schreiber and Jos Prickaerts
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During the last decennia, our understanding of the neurobiological processes underlying learning and memory has continuously improved, leading to the identification of targets for the development of memory-enhancing drugs. Here we review a class of drugs which has more recently been identified: the phosphodiesterase (PDE) inhibitors. An overview is given of the different PDEs that are known and we focus on three PDEs which have been identified as possible relevant targets for memory improvement: PDE2, PDE4 and PDE5. PDEs differ in the substrate, i.e. cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP), being hydrolyzed. Since these cyclic nucleotides have been suggested to play distinct roles in processes of memory, selective PDE inhibitors preventing the breakdown of cAMP and/or cGMP could improve memory. The present data suggest that PDE4 (cAMP) is involved in acquisition processes, although a possible role in late consolidation processes cannot be excluded. PDE5 (cGMP) is involved in early consolidation processes. Since PDE2 inhibition affects both cAMP and cGMP, PDE2 inhibitors may improve both memory processes. The field of PDEs is highly dynamic and new isoforms of PDEs are still being described. This may lead to the discovery and development of new memory enhancing drugs that selectively inhibit such isoforms. Such drugs may exert their effects only in specific brain areas and hence possess an improved side effect profile.
Progress in Current Non-Viral Carriers for Gene Delivery
Page: 81-97 (17)
Author: Yoko Shoji-Moskowitz, Daisuke Asai, Ami E.Iskandrian, Kota Kodama, Yoshiki Katayama and Hideki Nakashima
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Since the viral vector for gene therapy has serious problems, including oncogenesity and other adverse effects, non-viral carriers have attracted a great deal of attention. However, the most critical issue of gene delivery by non-viral carriers is the low-expression efficiencies of the desired gene. In order to apply non-viral carriers for gene therapy in practical clinical usage, the improvement of transfection efficiency is a prerequisite. We will summarize the current progress of non-viral delivery systems for gene therapy. Especially, we will address the applications of cationic lipids (lipoplex) and cationic polymers (polyplex) in vivo. Furthermore, there have been reported a disease-site-specific delivery system which responds to highly activated cellular signals, which is called a drug delivery system based on responses cellular signal (D-RECS). We will also introduce the current progress of D-RECS gene delivery which is activated by HIV protease in only HIV-infected cells.
Protein Transduction: Cell Penetrating Peptides and Their Therapeutic Applications
Page: 98-126 (29)
Author: Kylie M. Wagstaff and David A. Jans
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Cell penetrating proteins or peptides (CPPs) have the ability to cross the plasma membranes of mammalian cells in an apparently energy- and receptorindependent fashion. Although there is much debate over the mechanism by which this “protein transduction” occurs, the ability of CPPs to translocate rapidly into cells is being exploited to deliver a broad range of therapeutics including proteins, DNA, antibodies, oligonucleotides, imaging agents and liposomes in a variety of situations and biological systems. The current review looks at the delivery of many such molecules by various CPPs, and their potential therapeutic application in a wide range of areas. CPP ability to deliver different cargoes in a relatively efficient and non-invasive manner has implications as far reaching as drug delivery, gene transfer, DNA vaccination and beyond. Although many questions remain to be answered and limitations on the use of CPPs exist, it is clear that this emerging technology has much to offer in a clinical setting.
Design of Peptide-Based Vaccines for Cancer
Page: 127-166 (40)
Author: Geoffrey A. Pietersz, Dodie S. Pouniotis and Vasso Apostolopoulos
The immune system responds efficiently to bacteria, viruses and other agents however, the immune response to cancers is not as effective. In most cases other than specific genetic rearrangements leading to non-self proteins such as in leukemia and idiotypes in lymphoma, tumor associated proteins are self proteins and are not recognized by the immune system to prevent malignancy. In most cancers, patients develop antibodies and/or CTL-precursors to tumor associated antigens but are not effective in generating a therapeutic immune response. Adjuvants have been used with either whole tumors, subunits or peptides with the aim of increasing their immunity. Whole tumor antigens have certain advantages associated with it, such as ready availability as recombinant proteins, potential epitopes that can be presented by a number of MHC class I/II alleles and antibody development. The methods of identification of CD8 and CD4 epitopes either by use of epitope prediction algorithms or use of transgenic mice has made the use of defined synthetic peptides more attractive. The possibility to synthesize long peptides and introduce multiple epitopes (CD4 or CD8) from single or multiple antigens makes peptide a viable alternative to whole proteins. As an alternative to totally synthetic peptide constructs or polymers, polytopes have been generated by genetic engineering methods. In addition, to deliver immunogens to and to activate DC, receptor- mediated delivery of peptides using antibodies, cytokines and carbohydrates have been used. This review will encompass the various strategies, preclinical and clinical applications in designing peptide-based vaccines for cancer.
Inhibitors of Protein: Geranylgeranyl Transferases
Page: 167-233 (67)
Author: Farid El Oualid, Gijs A. van der Marel and Mark Overhand
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The enzyme protein:geranylgeranyl transferase-1 (PGGT-1 or GGTase-I) catalyzes the geranylgeranylation of cysteine residues near the C-termini of a variety of proteins, including most monomeric GTP binding precursor proteins belonging to the Rho, Rac and Rap subfamilies. These proteins are involved in signaling pathways controlling important processes such as cell differentiation and growth. In the framework of the development of therapeutics against disorders associated with aberrant cell proliferation, the interference with these signal transduction cascades has been a major focus of investigation. For instance, PGGT-1 inhibitors have shown promise in the treatment of cancer, smooth muscle hyperplasia as well as parasitic infections, such as malaria. In this chapter, we discuss the structural and mechanistic aspects of the protein:geranylgeranyl transferases and their importance with respect to the terpene metabolism. In view of the latter, several terpene based proteomic probes have been developed and applied. An extensive summary of reported inhibitors of PGGT-1, classified as natural products, peptide substrate (Ca1a2L box), terpene substrate (geranylgeranyl pyrophosphate) and others, is presented. The few known inhibitors of the other geranylgeranylating enzyme, protein:geranylgeranyl transferase-2 (PGGT-2) also known as Rab geranylgeranyl transferase are also included.
Voltage-Gated Sodium Channels: New Targets in Cancer Therapy?
Page: 234-256 (23)
Author: Ludovic Gillet, Sebastien Roger, Marie Potier, Lucie Brisson, Christophe Vandier, Pierre Besson and Jean-Yves Le Guennec
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Early detection and treatment of cancers have increased survival and improved clinical outcome. The development of metastases is often associated with a poor prognostic of survival. Finding early markers of metastasis and developing new therapies against their development is a great challenge. Since a few years, there is more evidence that ion channels are involved in the oncogenic process. Among these, voltage-gated sodium channels expressed in non-nervous or non-muscular organs are often associated with the metastatic behaviour of different cancers. The aim of this review is to describe the current knowledge on the functional expression of voltage-gated sodium channels and their biological roles in different cancers such as prostate, breast, lung (small cells and non-small cells) and leukaemia. As a conclusion, we develop conceptual approaches to understand how such channels can be involved in the metastatic process and conclude that blockers targeted toward these channels are promising new therapeutic solutions against metastatic cancers.
Recent Advances in Antiviral Agents: Antiviral Drug Discovery for Hepatitis Viruses
Page: 257-271 (15)
Author: Kyuichi Tanikawa
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Hepatitis B virus (HBV)- or hepatitis C virus (HCV)- associated liver diseases are now one of the important health problems in the world because of the high numbers of patients and the serious consequences. Recently, however, relatively effective treatments with antiviral agents have become available. Interferon (IFN) and several nucleotide analogs (lamivudine, adefovir, entecavir and tenofovir) are now approved for treatment of HBV-associated liver diseases and they have been shown to be fairly effective. The goal of treatments for HBVassociated liver disease is to achieve a clinical cure in as short a period as possible without producing resistance mutation of the virus.
In the case of HCV-associated liver diseases, Pegylated IFN (Peg IFN) + ribavirin combination therapy is the standard and most effective treatment with a sustained response of 60-70%. The goal of the treatments for these liver diseases is to induce the complete eradication of the infected virus and at present new anti HCV drugs targeting the molecular segments of the virus are under development. It is expected that the complete eradication of infected virus will be possible in most cases in the near future.
NO-Releasing Hybrids of Cardiovascular Drugs
Page: 272-308 (37)
Author: Alma Martelli, Simona Rapposelli, Maria C. Breschi and Vincenzo Calderone
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Nitric oxide (NO) is an endogenous compound, playing a fundamental role in the modulation of the function of cardiovascular system, where it induces vasorelaxing and antiplatelet responses mainly through the stimulation of guanylate cyclase and the increase of cGMP. Many drugs of common and old clinical use (for example, glycerol trinitrate and all the vasodilator nitrites and nitrates) act via the release of exogenous NO, thus mimcking the effects of the endogenous factor.
In the last years, a revision of the “one-compound-one-target” paradigm led pharmacologists and medicinal chemists to develop new classes of molecules, joining more pharmacodynamic properties. Among them, this innovative pharmacological/ pharmaceutical strategy produced hybrid drugs, with a dual mechanism of action: a) the slow release of nitric oxide and b) an other fundamental pharmacodynamic profile.
These drugs have been obtained with the insertion of appropriate NO-donor chemical groups (i.e. nitrate esters, nitrosothiols, etc.), linked to a known drug, through a variable spacer moiety.
These new pharmacodynamic hybrids present the advantage of joining to a main mechanism of action (for example, cyclooxigenase inhibition, beta-antagonism or ACE-inhibition) also a slow release of NO, useful either to reduce the adverse side effects (for example, the gastrotoxicity of NSAIDs) or to improve the effectiveness of the drug (for example, conferring direct vasorelaxing and antiplatelet effects to an ACE-inhibitor).
This review wishes to present the chemical features of NO-releasing hybrids of cardiovascular drugs and to explain the pharmacological improvements conferred by the addiction of the NO-donor properties.
Trends in the Development of New Drugs for Treatment of Benign Prostatic Hyperplasia
Page: 309-349 (41)
Author: Katarzyna Kulig and Barbara Malawska
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Benign prostatic hyperplasia (BPH) is a common condition in aging men that is characterized by nonmalignant enlargement of the prostate gland, and is frequently accompanied by urinary obstruction, and lower urinary tract symptoms (LUST). Currently pharmacotherapy of BPH is based on two classes of drugs: α1-adrenoceptor (α1-AR) antagonists and 5α-reductase inhibitors. It has been shown that α1-AR antagonists reduce symptom scores and increase peak urinary flow rates in BPH. Of particular importance for BPH therapy are uroselective α1-AR antagonists for which the hypotensive related side-effect caused by α1-AR blockade is reduced. 5α-Reductase inhibitors reduce prostate volume and symptom scores, while increasing peak urinary flow rates. This review describes new α1-AR antagonists and 5α-reductase inhibitors in the treatment of BPH and is updating paper published in Current Medicinal Chemistry (Katarzyna Kulig & Barbara Malawska, 2006, 13, 3395-3416). The new α1-AR antagonists represent various structures such as quinazolines, phenylethylamines, piperidines, and arylpiperazines. 5α-Reductase inhibitors are classified into two groups: steroidal and non-steroidal. The newer non-steroidal inhibitors include derivatives of benzo[c]quinolizinones, benzo[f]quinolonones, piperidones and carboxylic acids. Besides the development of new compounds belonging to the above mentioned groups, new agents for BPH treatment are sought among combined 5α-reductase/α1-AR inhibitors, endothelins, androgen receptors antagonists, growth factors, estrogens and phosphodiesterase isoenzymes as well as several phytomedicines, used for prevention and treatment of prostate disorders. These new agents can be used for the design of future targets and development of new drugs in the treatment of BPH. The discovery of a number of active leads may also ultimately help in developing new safe and effective drugs.
Targeting the Prostaglandin D2 Receptors DP1 and CRTH2 for Treatment of Inflammation
Page: 350-380 (31)
Author: Trond Ulven and Evi Kostenis
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The involvement of prostaglandin D2 (PGD2) in inflammatory diseases like allergy and asthma is well established, and blocking the effect of this mediator represents and interesting therapeutic approach for the treatment of such diseases. PGD2 is now known to act through two seven-transmembrane (7TM) receptors, DP1 (previously DP) and CRTH2 (DP2), which are also activated by several endogenous metabolites from the arachidonic acid cascade, making the regulatory system highly complex. There has recently been a considerable effort aimed at developing antagonists of the PGD2 receptors for treatment of inflammatory conditions like asthma and rhinitis, and especially CRTH2 has received much attention since its identification as the second high affinity PGD2 receptor in 2001. A number of potent and selective antagonists are now available for both receptors. This review will briefly discuss the biological background and validation of DP1 and CRTH2 as targets for antiinflammatory drugs, and then highlight developments in medicinal chemistry which have appeared in journals and patent applications in the last few years, and which have brought us closer to therapeutic applications of PGD2 receptor antagonists in various indications.
Privileged Structures as Leads in Medicinal Chemistry
Page: 381-422 (42)
Author: Luca Costantino and Daniela Barlocco
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Among the strategies that can lead to the discovery of new drugs, the identification and use of privileged structures, molecular fragments that are able to interact with more than one target, gained particular attention, in an attempt to find new drugs in a shorter time with respect to other strategies. These structures, that have been identified mainly by empirical observations, can target only a given protein family, or can be able to interact with more, unrelated targets. This review deals with structures not covered in recent papers on this topic, and emphasizes the importance of understanding the structure-target relationships, that confer the privileged status
Acetylcholinesterase Reprised: Molecular Modeling with the Whole Toolkit
Page: 423-456 (34)
Author: Gerald H. Lushington, Jian-Xin Guo and Margaret M. Hurley
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Molecular modeling efforts aimed at probing the structure, function and inhibition of the acetylcholinesterase enzyme have abounded in the last 15 years, largely due to the system's importance to medical conditions such as myasthenia gravis, Alzheimer's disease and Parkinson's disease, and well as its famous toxicological susceptibility to nerve agents. The complexity inherent in such a system with multiple complementary binding sites, critical dynamic effects and intricate mechanisms for enzymatic function and covalent inhibition, has led to an impressively diverse selection of simulation techniques being applied to the system, including quantum chemical mechanistic studies, molecular docking prediction of noncovalent complexes and their associated binding free energies, molecular dynamics conformational analysis and transport kinetics prediction, and quantitative structure activity relationship modeling to tie salient details together into a coherent predictive tool. Effective drug and prophylaxis design strategies for a complex target like this requires some understanding and appreciation for all of the above methods, thus it makes an excellent case study for multi-faceted pharmacological modeling. This paper reviews a sample of the more important studies on acetylcholinesterase and helps to elucidate their interdependencies. Potential future directions are introduced based on the special methodological needs of the acetylcholinesterase system and on emerging trends in molecular modeling.
&ldquo;Frontiers in Medicinal Chemistry&rdquo; is an Ebook series devoted to the review of areas of important topical interest to medicinal chemists and others in allied disciplines. &ldquo;Frontiers in Medicinal Chemistry&rdquo; covers all the areas of medicinal chemistry, including developments in rational drug design, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, chemoinformatics, and structure-activity relationships. Medicinal chemistry as a discipline is rapidly maturing. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. &ldquo;Frontiers in Medicinal Chemistry&rdquo; aims to contribute in a major way to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. This Ebook series is essential for any medicinal chemist who wishes to be kept informed and up-to-date with the latest and the most important advances.