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Pharmaceuticals, Volume 6, Issue 12 (December 2013) – 4 articles , Pages 1451-1575

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575 KiB  
Review
Antimicrobial Peptides
by Ali Adem Bahar and Dacheng Ren
Pharmaceuticals 2013, 6(12), 1543-1575; https://doi.org/10.3390/ph6121543 - 28 Nov 2013
Cited by 1101 | Viewed by 54085
Abstract
The rapid increase in drug-resistant infections has presented a serious challenge to antimicrobial therapies. The failure of the most potent antibiotics to kill “superbugs” emphasizes the urgent need to develop other control agents. Here we review the history and new development of antimicrobial [...] Read more.
The rapid increase in drug-resistant infections has presented a serious challenge to antimicrobial therapies. The failure of the most potent antibiotics to kill “superbugs” emphasizes the urgent need to develop other control agents. Here we review the history and new development of antimicrobial peptides (AMPs), a growing class of natural and synthetic peptides with a wide spectrum of targets including viruses, bacteria, fungi, and parasites. We summarize the major types of AMPs, their modes of action, and the common mechanisms of AMP resistance. In addition, we discuss the principles for designing effective AMPs and the potential of using AMPs to control biofilms (multicellular structures of bacteria embedded in extracellular matrixes) and persister cells (dormant phenotypic variants of bacterial cells that are highly tolerant to antibiotics). Full article
(This article belongs to the Special Issue Peptide Drug Discovery and Development)
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Figure 1
<p>Schematic representation of an α-helical AMP. This figure assumes the same α-helix propensity for all amino acids in the peptide structure. (<b>A</b>) Helical wheel projection of the AMP (top view). The angle between two consecutive amino acids in the sequence is 100 degree. Dotted lines show two adjacent amino acids in the primary structure. (<b>B</b>) Side view of the peptide. The distance between two adjacent amino acids, “n”, is 0.15 nm.</p>
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<p>Schematic representation of some action mechanisms of membrane-active AMPs.(<b>A</b>) Barrel-Stave model. AMP molecules insert themselves into the membrane perpendicularly. (<b>B</b>) Carpet model. Small areas of the membrane are coated with AMP molecules with hydrophobic sides facing inward leaving pores behind in the membrane. (<b>C</b>) Toroidal pore model. This model resembles the Barrel-stave model, but AMPs are always in contact with phospholipid head groups of the membrane. The blue color represents the hydrophobic portions of AMPs, while the red color represents the hydrophilic parts of the AMPs.</p>
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<p>Schematic representation of AMP resistance mechanisms. (<b>A</b>) Gram-positive bacteria resist AMPs via teichoic acid modification of LPS molecules and <span class="html-small-caps">l</span>-lysine modification of phospholipids. (<b>B</b>) Gram-negative bacteria resist AMPs by modifying LPS molecules with aminoarabinose or acylation of Lipid A unit of LPS molecules. (<b>C</b>) Bacteria express some positively charged proteins and integrate them in the membrane so positive charges repulse each other and bacteria can resist such AMPs. (<b>D</b>) Bacteria produce negatively charged proteins and secrete them into extracellular environment to bind and block AMPs. (<b>E</b>) The intracellular AMPs are extruded by efflux pumps. (<b>F</b>) The AMPs inside the cell are degraded by proteases.</p>
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567 KiB  
Review
Aptamer-Based Therapeutics: New Approaches to Combat Human Viral Diseases
by Ka-To Shum, Jiehua Zhou and John J. Rossi
Pharmaceuticals 2013, 6(12), 1507-1542; https://doi.org/10.3390/ph6121507 - 25 Nov 2013
Cited by 63 | Viewed by 14433
Abstract
Viruses replicate inside the cells of an organism and continuously evolve to contend with an ever-changing environment. Many life-threatening diseases, such as AIDS, SARS, hepatitis and some cancers, are caused by viruses. Because viruses have small genome sizes and high mutability, there is [...] Read more.
Viruses replicate inside the cells of an organism and continuously evolve to contend with an ever-changing environment. Many life-threatening diseases, such as AIDS, SARS, hepatitis and some cancers, are caused by viruses. Because viruses have small genome sizes and high mutability, there is currently a lack of and an urgent need for effective treatment for many viral pathogens. One approach that has recently received much attention is aptamer-based therapeutics. Aptamer technology has high target specificity and versatility, i.e., any viral proteins could potentially be targeted. Consequently, new aptamer-based therapeutics have the potential to lead a revolution in the development of anti-infective drugs. Additionally, aptamers can potentially bind any targets and any pathogen that is theoretically amenable to rapid targeting, making aptamers invaluable tools for treating a wide range of diseases. This review will provide a broad, comprehensive overview of viral therapies that use aptamers. The aptamer selection process will be described, followed by an explanation of the potential for treating virus infection by aptamers. Recent progress and prospective use of aptamers against a large variety of human viruses, such as HIV-1, HCV, HBV, SCoV, Rabies virus, HPV, HSV and influenza virus, with particular focus on clinical development of aptamers will also be described. Finally, we will discuss the challenges of advancing antiviral aptamer therapeutics and prospects for future success. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
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Figure 1
<p>(<b>A</b>) HIV-1 genome and (<b>B</b>) HIV-1 virion and potential antiviral targets.</p>
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<p>(<b>A</b>) Aptamer-siRNA conjugates. The 2'-F-modified gp120 aptamer was covalently appended to the sense strand of a <span class="html-italic">tat/rev</span> siRNA portion, which in turn was hybridized to the antisense strand. A 4-nt linker (CUCU) was inserted between the aptamer and siRNA portions to minimize steric interference of the gp120 aptamer with Dicer processing [<a href="#B143-pharmaceuticals-06-01507" class="html-bibr">143</a>]. (<b>B</b>) Aptamer-stick-siRNA chimeras. The 2'-F-modified gp120 aptamer and the siRNAs are shown. The antisense of the siRNA is linked to the aptamer portion by the stick sequence, which consists of 16 nt appended to the 3' end of the gp120 aptamer, allowing complementary base-pairing of one of the two siRNA strands with the aptamers [<a href="#B83-pharmaceuticals-06-01507" class="html-bibr">83</a>].</p>
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<p>Representation of the secondary structure of HCV IRES. Structural domains are shown as I–IV. The HH363 cleavage site is indicated by an arrow.</p>
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315 KiB  
Review
Glioblastoma Multiforme Therapy and Mechanisms of Resistance
by Yulian P. Ramirez, Jessica L. Weatherbee, Richard T. Wheelhouse and Alonzo H. Ross
Pharmaceuticals 2013, 6(12), 1475-1506; https://doi.org/10.3390/ph6121475 - 25 Nov 2013
Cited by 189 | Viewed by 17057
Abstract
Glioblastoma multiforme (GBM) is a grade IV brain tumor characterized by a heterogeneous population of cells that are highly infiltrative, angiogenic and resistant to chemotherapy. The current standard of care, comprised of surgical resection followed by radiation and the chemotherapeutic agent temozolomide, only [...] Read more.
Glioblastoma multiforme (GBM) is a grade IV brain tumor characterized by a heterogeneous population of cells that are highly infiltrative, angiogenic and resistant to chemotherapy. The current standard of care, comprised of surgical resection followed by radiation and the chemotherapeutic agent temozolomide, only provides patients with a 12–14 month survival period post-diagnosis. Long-term survival for GBM patients remains uncommon as cells with intrinsic or acquired resistance to treatment repopulate the tumor. In this review we will describe the mechanisms of resistance, and how they may be overcome to improve the survival of GBM patients by implementing novel chemotherapy drugs, new drug combinations and new approaches relating to DNA damage, angiogenesis and autophagy. Full article
(This article belongs to the Special Issue Chemotherapeutic Agents)
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<p>Novel TMZ-like drugs.</p>
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<p>Prodrug activation of temozolomide.</p>
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<p>Biological fate of methyldiazonium ions.</p>
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<p>Mechanism of prodrug activation and action of carmustine.</p>
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<p>Mechanism of action of MGMT and structures of the two clinically tested MGMT inactivators.</p>
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<p>Reaction of DP86 in phosphate buffer pD = 7.4. * Sites of <sup>13</sup>C labelling.</p>
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252 KiB  
Review
Effect of Essential Oils on Pathogenic Bacteria
by Filomena Nazzaro, Florinda Fratianni, Laura De Martino, Raffaele Coppola and Vincenzo De Feo
Pharmaceuticals 2013, 6(12), 1451-1474; https://doi.org/10.3390/ph6121451 - 25 Nov 2013
Cited by 1462 | Viewed by 61223
Abstract
The increasing resistance of microorganisms to conventional chemicals and drugs is a serious and evident worldwide problem that has prompted research into the identification of new biocides with broad activity. Plants and their derivatives, such as essential oils, are often used in folk [...] Read more.
The increasing resistance of microorganisms to conventional chemicals and drugs is a serious and evident worldwide problem that has prompted research into the identification of new biocides with broad activity. Plants and their derivatives, such as essential oils, are often used in folk medicine. In nature, essential oils play an important role in the protection of plants. Essential oils contain a wide variety of secondary metabolites that are capable of inhibiting or slowing the growth of bacteria, yeasts and moulds. Essential oils and their components have activity against a variety of targets, particularly the membrane and cytoplasm, and in some cases, they completely change the morphology of the cells. This brief review describes the activity of essential oils against pathogenic bacteria. Full article
(This article belongs to the Special Issue Antimicrobial Agents)
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<p>Schematic of the envelopes of Gram-positive (on the right) and Gram-negative bacteria (on the left).</p>
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<p>Mechanism of action and target sites of the essential oils on microbial cells.</p>
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