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OPEN ACCESS PLUS
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Contents
Pp. 2534 - 2545
Jarl Underhaug, Oscar Aubi and Aurora Martinez
[Open Access Plus] |
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Phenylketonuria (PKU) is a loss-of-function inborn error of metabolism. As many other inherited diseases the main pathologic mechanism in PKU is an enhanced tendency of the mutant phenylalanine hydroxylase (PAH) to misfold and undergo ubiquitin-dependent degradation. Recent alternative approaches with therapeutic potential for PKU aim at correcting the PAH misfolding, and in this respect pharmacological chaperones are the focus of increasing interest. These compounds, which often resemble the natural ligands and show mild competitive inhibition, can rescue the misfolded proteins by stimulating their renaturation in vivo. For PKU, a few studies have proven the stabilization of PKU-mutants in vitro, in cells, and in mice by pharmacological chaperones, which have been found either by using the tetrahydrobiopterin (BH4) cofactor as query structure for shape-focused virtual screening or by high-throughput screening of small compound libraries. Both approaches have revealed a number of compounds, most of which bind at the iron-binding site, competitively with respect to BH4. Furthermore, PAH shares a number of ligands, such as BH4, amino acid substrates and inhibitors, with the other aromatic amino acid hydroxylases: the neuronal/neuroendocrine enzymes tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPHs). Recent results indicate that the PAH-targeted pharmacological chaperones should also be tested on TH and the TPHs, and eventually be derivatized to avoid unwanted interactions with these other enzymes. After derivatization and validation in animal models, the PAH-chaperoning compounds represent novel possibilities in the treatment of PKU.
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Pp. 2002 - 2012
Sara E. Nichols, Robert V. Swift and Rommie E. Amaro
[Open Access Plus] |
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Although the motions of proteins are fundamental for their function, for pragmatic reasons, the consideration of protein elasticity has traditionally been neglected in drug discovery and design. This review details protein motion, its relevance to biomolecular interactions and how it can be sampled using molecular dynamics simulations. Within this context, two major areas of research in structure-based prediction that can benefit from considering protein flexibility, binding site detection and molecular docking, are discussed. Basic classification metrics and statistical analysis techniques, which can facilitate performance analysis, are also reviewed. With hardware and software advances, molecular dynamics in combination with traditional structure-based prediction methods can potentially reduce the time and costs involved in the hit identification pipeline.
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Pp. 473 - 483
Arnab K. Chatterjee and Bryan K.S. Yeung
[Open Access Plus] |
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Antimalarial drug discovery has historically benefited from the whole-cell (phenotypic) screening approach to identify lead molecules in the search for new drugs. However over the past two decades there has been a shift in the pharmaceutical industry to move away from whole-cell screening to target-based approaches. As part of a Wellcome Trust and Medicines for Malaria Venture (MMV) funded consortium to discover new blood-stage antimalarials, we used both approaches to identify new antimalarial chemotypes, two of which have progressed beyond the lead optimization phase and display excellent in vivo efficacy in mice. These two advanced series were identified through a cell-based optimization devoid of target information and in this review we summarize the advantages of this approach versus a target-based optimization. Although the each lead optimization required slightly different medicinal chemistry strategies, we observed some common issues across the different the scaffolds which could be applied to other cell based lead optimization programs.
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Pp. 400 - 407
David H. Peyton
[Open Access Plus] |
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This short review tells the story of how Reversed Chloroquine drugs (RCQs) were developed. These are hybrid molecules, made by combining the quinoline nucleus from chloroquine (CQ) with moieties which are designed to inhibit efflux via known transporters in the membrane of the digestive vacuole of the malaria parasite. The resulting RCQ drugs can have potencies exceeding that of CQ, while at the same time having physical chemical characteristics that may make them favorable as partner drugs in combination therapies. The need for such novel antimalarial drugs will continue for the foreseeable future.
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Pp. 2457 - 2471
Igor Timofeev and Sylvain Chauvette
[Open Access Plus] |
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This article starts with a brief review of the thalamocortical system architecture, which is composed of the projecting thalamic nuclei, the thalamic reticular nucleus, and the neocortex. Then we provide a description of the three states of vigilances followed by a detailed review of major brain rhythms present in the thalamocortical system, ranging from very slow to very fast oscillations. We provide descriptions of known mechanisms and hypotheses for unknown mechanisms for the generation of the different rhythms. The last part offers a detailed review on sleep slow oscillation describing its properties in the thalamocortical system, proposing a mechanism of generation of active states and a description of their propagation.
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Pp. 1292 - 1300
Andrew L. Hopkins, G. Richard Bickerton, Ian M. Carruthers, Stephen K. Boyer, Harvey Rubin and John P. Overington
[Open Access Plus] |
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Pandemic, epidemic and endemic infectious diseases are united by a common problem: how do we rapidly and cost-effectively identify potential pharmacological interventions to treat infections? Given the large number of emerging and neglected infectious diseases and the fact that they disproportionately afflict the poorest members of the global society, new ways of thinking are required to develop high productivity discovery systems that can be applied to a large number of pathogens. The growing availability of parasite genome data provides the basis for developing methods to prioritize, a priori potential drug targets and analyze the pharmacological landscape of an infectious disease. Thus the overall objective of infectious disease informatics is to enable the rapid generation of plausible, novel medical hypotheses of testable pharmacological experiments, by uncovering undiscovered relationships in the wealth of biomedical literature and databases that were collected for other purposes. In particular our goal is to identify potential drug targets present in a pathogen genome and prioritize which pharmacological experiments are most likely to discover drug-like lead compounds rapidly against a pathogen (i.e. which specific compounds and drug targets should be screened, in which assays and where they can be sourced). An integral part of the challenge is the development and integration of methods to predict druggability, essentiality, synthetic lethality and polypharmocology in pathogen genomes, while simultaneously integrating the inevitable issues of chemical tractability and the potential for acquired drug resistance from the start.
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Pp. 1275 - 1283
Paul G. Wyatt, Ian H. Gilbert, Kevin D. Read and Alan H. Fairlamb
[Open Access Plus] |
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The discovery of drugs is a lengthy, high-risk and expensive business taking at least 12 years and is estimated to cost upwards of US$800 million for each drug to be successfully approved for clinical use. Much of this cost is driven by the late phase clinical trials and therefore the ability to terminate early those projects destined to fail is paramount to prevent unwanted costs and wasted effort. Although neglected diseases drug discovery is driven more by unmet medical need rather than financial considerations, the need to minimise wasted money and resources is even more vital in this under- funded area. To ensure any drug discovery project is addressing the requirements of the patients and health care providers and delivering a benefit over existing therapies, the ideal attributes of a novel drug needs to be pre-defined by a set of criteria called a target product profile. Using a target product profile the drug discovery process, clinical study design, and compound characteristics can be defined all the way back through to the suitability or druggability of the intended biochemical target. Assessment and prioritisation of the most promising targets for entry into screening programmes is crucial for maximising chances of success.
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Pp. 1079 - 1087
Kazuo Suzuki and Anthony D. Kelleher
[Open Access Plus] |
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Small RNA molecules, including small interfering RNA (siRNA) and micro RNA (miRNA), have rapidly emerged as important regulators of gene expression. Recent articles have demonstrated RNA mediated complex induced transcriptional gene silencing (TGS) occurring in the nucleus. Originally the small RNA mediated TGS pathway has been reported in yeast and plants, currently a number of articles strongly suggest that this newly established gene silencing mechanism is present in mammals. RNA mediated TGS has been reported for various human promoters including inhibition of tumor susceptibility genes, X-chromosome inactivation and suppression of human chemokine receptor. Small RNAs can inhibit human viral infection through the TGS pathway. Prolonged HIV-1 transcriptional gene silencing by an RNA duplex targeting a sequence located within the HIV-1 promoter has been reported initially using a susceptible adherent cell line model and recently prolonged suppression of productive HIV-1 infection in a T-cell line model has been demonstrated by a retrovirally delivered short-hairpin RNA (shRNA) targeting the same region. RNA mediated gene silencing in HIV-1 infection can induce heterochromatin (closed) structure in the promoter regions, which is consistent to those changes seen in studies of various RNA directed TGS in various human promoter regions. More recent observations suggest transcriptional activation can be induced through RNA duplexes targeting the human promoter of E-cadherin, p21 and the progesterone receptor. Although the precise mechanisms of how RNA mediated transcriptional gene silencing or activation functions has yet to be elucidated, this review describes linkage of small RNA mediated gene regulation and induction of epigenetic regulation in the promoter region in mammals.
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Pp. 724 - 737
Zhulun Wang, Holger Wesche, Tracey Stevens, Nigel Walker and Wen-Chen Yeh
[Open Access Plus] |
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Interleukin-1 receptor-associated kinases (IRAKs) are key components in the signal transduction pathways utilized by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), and Toll-like receptors (TLRs). Out of four members in the mammalian IRAK family, IRAK-4 is considered to be the “master IRAK”, the only family member indispensable for IL-1R/TLR signaling. In humans, mutations resulting in IRAK-4 deficiency have been linked to susceptibility to bacterial infections, especially recurrent pyogenic bacterial infections. Furthermore, knock-in experiments by several groups have clearly demonstrated that IRAK-4 requires its kinase activity for its function. Given the critical role of IRAK-4 in inflammatory processes, modulation of IRAK-4 kinase activity presents an attractive therapeutic approach for the treatment of immune and inflammatory diseases. The recent success in the determination of the 3-dimensional structure of the IRAK-4 kinase domain in complex with inhibitors has facilitated the understanding of the mechanistic role of IRAK-4 in immunity and inflammation as well as the development of specific IRAK-4 kinase inhibitors. In this article, we review the biological function of IRAK-4, the structural characteristics of the kinase domain, and the development of small molecule inhibitors targeting the kinase activity. We also review the key pharmacophores required for several classes of inhibitors as well as important features for optimal protein/inhibitor interactions. Lastly, we summarize how these insights can be translated into strategies to develop potent IRAK-4 inhibitors with desired properties as new anti-inflammatory therapeutic agents.
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Pp. 1137 - 1144
Trevor J. Hallam, Carl Spana, Dennis C. Earle, Annette M. Shadiack and Shubh D. Sharma
[Open Access Plus] |
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Melanocortinergic agents are currently being investigated for a possible therapeutic role in male and female sexual dysfunction. These investigations were sparked by findings that systemic administration of a synthetic analog of alpha-MSH, MT-II, causes penile erections in a variety of species, including humans. Several other melanocortinergic agents including HP-228, THIQ, and bremelanotide (PT-141) have since been shown to have erectogenic properties thought to be due to binding to melanocortin receptors in the central nervous system, particularly the hypothalamus. Bremelanotide, a nasally administered synthetic peptide, is the only melanocortinergic agent that has been clinically studied in both males and females. Data from Phase II clinical trials of bremelanotide support the use of melanocortin-based therapy for erectile dysfunction. Studies using animal models have demonstrated that precopulatory behaviors in female rats analogous to sexual arousal are evoked, and preliminary clinical data also suggest a role in promoting sexual desire and arousal in women. Based on bremelanotide clinical experience, administration of a melanocortin agonist is well tolerated and not associated the hypotension observed with phosphodiesterase-5 inhibitors currently used to treat erectile dysfunction. This review discusses investigations of melanocortin agonists for the treatment of sexual dysfunction with emphasis on proposed sites and mechanisms of action in the central nervous system that appear to be involved in melanocortinergic modulation of sexual function. Current research validates use of melanocortinergic agents for the treatment of both male and female sexual dysfunction.
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Pp. 651 - 660
James E. Summerton
[Open Access Plus] |
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Generally a gene knockdown agent should achieve high sequence specificity and should lack off-target effects (non-antisense effects due to interactions with structures other than gene transcripts). Three major gene knockdown types are compared with respect to offtarget effects and sequence specificities: 1) phosphorothioate-linked DNA (S-DNA); 2) short interfering RNA (siRNA); and, 3) Morpholino. S-DNAs cause multiple off-target effects, largely because their backbone sulfurs bind to many different proteins. S-DNAs also achieve poor sequence specificity because S-DNA/RNA duplexes as short as 7 base-pairs are cleaved by RNase H. siRNAs cause several off-target effects, but improved designs may soon avoid such effects. siRNAs also provide only limited sequence specificity because their short guide sequences largely determine which gene transcripts will be blocked or cleaved, and those guide sequences appear to recognize insufficient sequence information to uniquely target a selected gene transcript. This specificity limitation is inherent in their mechanism of action and so probably cannot be greatly improved. Morpholinos are virtually free of off-target effects - probably because they cannot interact electrostatically with proteins. Morpholinos also achieve exquisite sequence specificity - in large part because they must bind at least about 14 to 15 contiguous bases to block a gene transcript, and this constitutes sufficient sequence information to uniquely target a selected gene transcript. Because of their freedom from off-target effects, exquisite sequence specificity, complete stability in biological systems, and highly predictable targeting, Morpholinos dominate the most demanding of all gene knockdown applications, studies in developing embryos.
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