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Special Issue "Aptamer-Based Therapeutics"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (30 June 2013)

Special Issue Editor

Guest Editor
Dr. Sotiris Missailidis

Department of Chemistry and Analytical Sciences, The Open University, Walton Hall, Milton Keynes, UK
Interests: pharmacogenomics; molecular recognition; biomarkers; DNA biomimetics; aptamers as DNA targeting; therapeutic and imaging agents; inflammation and cancer; organometallic drug; aptamers as therapeutic and diagnostic agents or as recognition elements in biosensor development

Special Issue Information

Dear Colleagues,

We invite authors to submit papers to Pharmaceuticals in the exciting field of Aptamer research. This special issue is to include original papers and review articles on basic or clinical research on aptamers, including aptamer selection methodologies, aptamer conjugates, aptamer nanoparticles, spiegelmers, peptide aptamers, locked aptamers and different aptamer applications, including applications in diagnostics, imaging, therapy, sensors or other technology development, aptamer pharmacology, biomarker discovery or clinical applications.

Dr. Sotiris Missailidis
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).

Keywords

  • aptamer Selection
  • SELEX
  • aptamer conjugates
  • aptamer nanoparticles
  • spiegelmers
  • peptide aptamers
  • DNA aptamers
  • RNA aptamer
  • aptasensors
  • photoaptamers
  • locked aptamers
  • aptamer conjugates
  • aptamer nanoparticles
  • aptamer diagnostics
  • aptamer therapeutics
  • aptamer radiopharmaceuticals
  • aptamers in oncology
  • aptamer metabolism
  • aptamer pharmacology
  • clinical trials

Published Papers (11 papers)

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Research

Jump to: Review

Open AccessArticle Structural and Affinity Analyses of G-Quadruplex DNA Aptamers for Camptothecin Derivatives
Pharmaceuticals 2013, 6(9), 1082-1093; doi:10.3390/ph6091082
Received: 1 July 2013 / Revised: 11 August 2013 / Accepted: 26 August 2013 / Published: 29 August 2013
Cited by 6 | PDF Full-text (783 KB) | HTML Full-text | XML Full-text
Abstract
We recently selected DNA aptamers that bind to camptothecin (CPT) and CPT derivatives from a 70-mer oligodeoxyribonucleotide (ODN) library using the Systematic Evolution of Ligands by EXponential enrichment (SELEX) method. The target-binding activity of the obtained 70-mer CPT-binding DNA aptamer, termed CA-70, [...] Read more.
We recently selected DNA aptamers that bind to camptothecin (CPT) and CPT derivatives from a 70-mer oligodeoxyribonucleotide (ODN) library using the Systematic Evolution of Ligands by EXponential enrichment (SELEX) method. The target-binding activity of the obtained 70-mer CPT-binding DNA aptamer, termed CA-70, which contains a 16-mer guanine (G)-core motif (G3TG3TG3T2G3) that forms a three-tiered G-quadruplex, was determined using fluorescence titration. In this study, truncated fragments of CA-70 that all have the G-core motif, CA-40, -20, -19, -18A, -18B, -17, and -16, were carefully analyzed. We found that CA-40 retained the target-binding activity, whereas CA-20, -19, and -18B exhibited little or no binding activities. Further, not only CA-18A but also the shorter length fragments CA-17 and -16 clearly retained the binding activity, indicating that tail strands of the G-quadruplex structure can significantly affect the target binding of G-quadruplex DNA aptamers. Further analyses using circular dichroism (CD) spectroscopy and fluorescence polarization (FP) assay were conducted to investigate the structure and affinity of G-quadruplex DNA aptamers. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessArticle The Inhibition of Stat5 by a Peptide Aptamer Ligand Specific for the DNA Binding Domain Prevents Target Gene Transactivation and the Growth of Breast and Prostate Tumor Cells
Pharmaceuticals 2013, 6(8), 960-987; doi:10.3390/ph6080960
Received: 8 July 2013 / Revised: 14 August 2013 / Accepted: 16 August 2013 / Published: 20 August 2013
Cited by 7 | PDF Full-text (1590 KB) | HTML Full-text | XML Full-text
Abstract
The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, [...] Read more.
The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessArticle Anti-HCV RNA Aptamers Targeting the Genomic cis-Acting Replication Element
Pharmaceuticals 2012, 5(1), 49-60; doi:10.3390/ph5010049
Received: 28 November 2011 / Revised: 15 December 2011 / Accepted: 22 December 2011 / Published: 28 December 2011
Cited by 3 | PDF Full-text (456 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis C virus (HCV) replication is dependent on the existence of several highly conserved functional genomic RNA domains. The cis-acting replication element (CRE), located within the 3' end of the NS5B coding region of the HCV genome, has been shown essential [...] Read more.
Hepatitis C virus (HCV) replication is dependent on the existence of several highly conserved functional genomic RNA domains. The cis-acting replication element (CRE), located within the 3' end of the NS5B coding region of the HCV genome, has been shown essential for efficient viral replication. Its sequence and structural features determine its involvement in functional interactions with viral RNA-dependent RNA polymerase and distant RNA domains of the viral genome. This work reports the use of an in vitro selection strategy to select aptamer RNA molecules against the complete HCV-CRE. After six selection cycles, five potential target sites were identified within this domain. Inhibition assays using a sample of representative aptamers showed that the selected RNAs significantly inhibit the replication (>80%) of a subgenomic HCV replicon in Huh-7 cell cultures. These results highlight the potential of aptamer RNA molecules as therapeutic antiviral agents. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessArticle RNA Detection in Live Bacterial Cells Using Fluorescent Protein Complementation Triggered by Interaction of Two RNA Aptamers with Two RNA-Binding Peptides
Pharmaceuticals 2011, 4(3), 494-508; doi:10.3390/ph4030494
Received: 28 December 2010 / Revised: 17 January 2011 / Accepted: 11 February 2011 / Published: 10 March 2011
Cited by 10 | PDF Full-text (550 KB) | HTML Full-text | XML Full-text
Abstract
Many genetic and infectious diseases can be targeted at the RNA level as RNA is more accessible than DNA. We seek to develop new approaches for detection and tracking RNA in live cells, which is necessary for RNA-based diagnostics and therapy. We [...] Read more.
Many genetic and infectious diseases can be targeted at the RNA level as RNA is more accessible than DNA. We seek to develop new approaches for detection and tracking RNA in live cells, which is necessary for RNA-based diagnostics and therapy. We recently described a method for RNA visualization in live bacterial cells based on fluorescent protein complementation [1-3]. The RNA is tagged with an RNA aptamer that binds an RNA-binding protein with high affinity. This RNA-binding protein is expressed as two split fragments fused to the fragments of a split fluorescent protein. In the presence of RNA the fragments of the RNA-binding protein bind the aptamer and bring together the fragments of the fluorescent protein, which results in its re-assembly and fluorescence development [1-3]. Here we describe a new version of the RNA labeling method where fluorescent protein complementation is triggered by paired interactions of two different closely-positioned RNA aptamers with two different RNA-binding viral peptides. The new method, which has been developed in bacteria as a model system, uses a smaller ribonucleoprotein complementation complex, as compared with the method using split RNA-binding protein, and it can potentially be applied to a broad variety of RNA targets in both prokaryotic and eukaryotic cells. We also describe experiments exploring background fluorescence in these RNA detection systems and conditions that improve the signal-to-background ratio. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)

Review

Jump to: Research

Open AccessReview Aptamer-Based Therapeutics: New Approaches to Combat Human Viral Diseases
Pharmaceuticals 2013, 6(12), 1507-1542; doi:10.3390/ph6121507
Received: 17 October 2013 / Revised: 12 November 2013 / Accepted: 15 November 2013 / Published: 25 November 2013
Cited by 12 | PDF Full-text (567 KB) | HTML Full-text | XML Full-text
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 [...] 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)
Open AccessReview A Review of Therapeutic Aptamer Conjugates with Emphasis on New Approaches
Pharmaceuticals 2013, 6(3), 340-357; doi:10.3390/ph6030340
Received: 16 February 2013 / Revised: 9 March 2013 / Accepted: 11 March 2013 / Published: 19 March 2013
Cited by 27 | PDF Full-text (458 KB) | HTML Full-text | XML Full-text
Abstract
The potential to emulate or enhance antibodies with nucleic acid aptamers while lowering costs has prompted development of new aptamer-protein, siRNA, drug, and nanoparticle conjugates. Specific focal points of this review discuss DNA aptamers covalently bound at their 3' ends to various [...] Read more.
The potential to emulate or enhance antibodies with nucleic acid aptamers while lowering costs has prompted development of new aptamer-protein, siRNA, drug, and nanoparticle conjugates. Specific focal points of this review discuss DNA aptamers covalently bound at their 3' ends to various proteins for enhanced stability and greater pharmacokinetic lifetimes in vivo. The proteins can include Fc tails of IgG for opsonization, and the first component of complement (C1q) to trigger complement-mediated lysis of antibiotic-resistant Gram negative bacteria, cancer cells and possibly some parasites during vulnerable stages. In addition, the 3' protein adduct may be a biotoxin, enzyme, or may simply be human serum albumin (HSA) or a drug known to bind HSA, thereby retarding kidney and other organ clearance and inhibiting serum exonucleases. In this review, the author summarizes existing therapeutic aptamer conjugate categories and describes his patented concept for PCR-based amplification of double-stranded aptamers followed by covalent attachment of proteins or other agents to the chemically vulnerable overhanging 3' adenine added by Taq polymerase. PCR amplification of aptamers could dramatically lower the current $2,000/gram cost of parallel chemical oligonucleotide synthesis, thereby enabling mass production of aptamer-3'-protein or drug conjugates to better compete against expensive humanized monoclonal antibodies. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessReview Selecting Molecular Recognition. What Can Existing Aptamers Tell Us about Their Inherent Recognition Capabilities and Modes of Interaction?
Pharmaceuticals 2012, 5(5), 493-513; doi:10.3390/ph5050493
Received: 5 March 2012 / Revised: 19 April 2012 / Accepted: 10 May 2012 / Published: 18 May 2012
Cited by 4 | PDF Full-text (959 KB) | HTML Full-text | XML Full-text
Abstract
The use of nucleic acid derived aptamers has rapidly expanded since the introduction of SELEX in 1990. Nucleic acid aptamers have demonstrated their ability to target a broad range of molecules in ways that rival antibodies, but advances have been very uneven [...] Read more.
The use of nucleic acid derived aptamers has rapidly expanded since the introduction of SELEX in 1990. Nucleic acid aptamers have demonstrated their ability to target a broad range of molecules in ways that rival antibodies, but advances have been very uneven for different biochemical classes of targets, and clinical applications have been slow to emerge. What sets different aptamers apart from each other and from rivaling molecular recognition platforms, specifically proteins? What advantages do aptamers as a reagent class offer, and how do the chemical properties and selection procedures of aptamers influence their function? Do the building blocks of nucleic acid aptamers dictate inherent limitations in the nature of molecular targets, and do existing aptamers give us insight in how these challenges might be overcome? This review is written as an introduction for potential endusers of aptamer technology who are evaluating the advantages of aptamers as a versatile, affordable, yet highly expandable platform to target a broad range of biological processes or interactions. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessReview Coupling Aptamers to Short Interfering RNAs as Therapeutics
Pharmaceuticals 2011, 4(11), 1434-1449; doi:10.3390/ph4111434
Received: 22 September 2011 / Revised: 13 October 2011 / Accepted: 24 October 2011 / Published: 27 October 2011
Cited by 4 | PDF Full-text (254 KB) | HTML Full-text | XML Full-text
Abstract
RNA-based approaches are among the most promising strategies aimed at developing safer and more effective therapeutics. RNA therapeutics include small non-coding miRNAs, small interfering RNA, RNA aptamers and more recently, small activating RNAs. However, major barriers exist to the use of RNAs [...] Read more.
RNA-based approaches are among the most promising strategies aimed at developing safer and more effective therapeutics. RNA therapeutics include small non-coding miRNAs, small interfering RNA, RNA aptamers and more recently, small activating RNAs. However, major barriers exist to the use of RNAs as therapeutics such as resistance to nucleases present in biological fluids, poor chemical stability, need of specific cell targeted delivery and easy entry into the cell. Such issues have been addressed by several recent reports that show the possibility of introducing chemical modifications in small RNAs to stabilize the molecular conformation and increase by several fold their integrity, while still preserving the functional activity. Further, several aptamers have been developed as excellent candidates for the specific recognition of cell surface targets. In the last few years, by taking advantage of recent advances in the small RNA field, molecular bioconjugates have been designed that permit specific targeting and may act as cargoes for cell internalization of small RNAs acting on gene expression that will be discussed in this review. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessReview Methods To Identify Aptamers against Cell Surface Biomarkers
Pharmaceuticals 2011, 4(9), 1216-1235; doi:10.3390/ph4091216
Received: 1 August 2011 / Revised: 2 September 2011 / Accepted: 9 September 2011 / Published: 20 September 2011
Cited by 23 | PDF Full-text (805 KB) | HTML Full-text | XML Full-text
Abstract
Aptamers are nucleic acid-based ligands identified through a process of molecular evolution named SELEX (Systematic Evolution of Ligands by Exponential enrichment). During the last 10-15 years, numerous aptamers have been developed specifically against targets present on or associated with the surface of [...] Read more.
Aptamers are nucleic acid-based ligands identified through a process of molecular evolution named SELEX (Systematic Evolution of Ligands by Exponential enrichment). During the last 10-15 years, numerous aptamers have been developed specifically against targets present on or associated with the surface of human cells or infectious pathogens such as viruses, bacteria, fungi or parasites. Several of the aptamers have been described as potent probes, rivalling antibodies, for use in flow cytometry or microscopy. Some have also been used as drugs by inhibiting or activating functions of their targets in a manner similar to neutralizing or agonistic antibodies. Additionally, it is straightforward to conjugate aptamers to other agents without losing their affinity and they have successfully been used in vitro and in vivo to deliver drugs, siRNA, nanoparticles or contrast agents to target cells. Hence, aptamers identified against cell surface biomarkers represent a promising class of ligands. This review presents the different strategies of SELEX that have been developed to identify aptamers for cell surface-associated proteins as well as some of the methods that are used to study their binding on living cells. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessReview Aptamer-Gated Nanoparticles for Smart Drug Delivery
Pharmaceuticals 2011, 4(8), 1137-1157; doi:10.3390/ph4081137
Received: 6 July 2011 / Revised: 4 August 2011 / Accepted: 11 August 2011 / Published: 15 August 2011
Cited by 26 | PDF Full-text (1106 KB) | HTML Full-text | XML Full-text
Abstract
Aptamers are functional nucleic acid sequences which can bind specific targets. An artificial combinatorial methodology can identify aptamer sequences for any target molecule, from ions to whole cells. Drug delivery systems seek to increase efficacy and reduce side-effects by concentrating the therapeutic [...] Read more.
Aptamers are functional nucleic acid sequences which can bind specific targets. An artificial combinatorial methodology can identify aptamer sequences for any target molecule, from ions to whole cells. Drug delivery systems seek to increase efficacy and reduce side-effects by concentrating the therapeutic agents at specific disease sites in the body. This is generally achieved by specific targeting of inactivated drug molecules. Aptamers which can bind to various cancer cell types selectively and with high affinity have been exploited in a variety of drug delivery systems for therapeutic purposes. Recent progress in selection of cell-specific aptamers has provided new opportunities in targeted drug delivery. Especially functionalization of nanoparticles with such aptamers has drawn major attention in the biosensor and biomedical areas. Moreover, nucleic acids are recognized as an attractive building materials in nanomachines because of their unique molecular recognition properties and structural features. A active controlled delivery of drugs once targeted to a disease site is a major research challenge. Stimuli-responsive gating is one way of achieving controlled release of nanoparticle cargoes. Recent reports incorporate the structural properties of aptamers in controlled release systems of drug delivering nanoparticles. In this review, the strategies for using functional nucleic acids in creating smart drug delivery devices will be explained. The main focus will be on aptamer-incorporated nanoparticle systems for drug delivery purposes in order to assess the future potential of aptamers in the therapeutic area. Special emphasis will be given to the very recent progress in controlled drug release based on molecular gating achieved with aptamers. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessReview Metallo-β-Lactamases and Aptamer-Based Inhibition
Pharmaceuticals 2011, 4(2), 419-428; doi:10.3390/ph4020419
Received: 14 January 2011 / Revised: 8 February 2011 / Accepted: 16 February 2011 / Published: 18 February 2011
Cited by 7 | PDF Full-text (358 KB) | HTML Full-text | XML Full-text
Abstract
An evolution of antibiotic-resistant bacteria has resulted in the need for new antibiotics. β-Lactam based drugs are the most predominantly prescribed antibiotics to combat bacterial infections; however, production of β-lactamases, which catalyze the hydrolysis of the β-lactam bond of this class of [...] Read more.
An evolution of antibiotic-resistant bacteria has resulted in the need for new antibiotics. β-Lactam based drugs are the most predominantly prescribed antibiotics to combat bacterial infections; however, production of β-lactamases, which catalyze the hydrolysis of the β-lactam bond of this class of antibiotics, by pathogenic bacteria such as Bacillus cereus, are rendering them useless. Some inhibitors of β-lactamases have been found, but there are no inhibitors against a class of β-lactamases known as metallo-β-lactamases, and it has been reported that the number of bacteria that produce metallo-β-lactamases is on the rise. Finding inhibitors of metallo-β-lactamases is thus an urgent necessity. One way to approach the problem is by employing the combinatorial method SELEX. The SELEX method is significant in discovering and producing new classes of inhibitors, as well as providing insight into the development of these inhibitors and paves the way for future aptamer applications that further novel drug discovery. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title: Coupling Aptamers to short Interfering RNAs as Therapeutics
Authors: Vittorio de Franciscis and Laura Cerchia
Affiliation: Istituto per l’Endocrinologia e l’Oncologia Sperimentale del CNR ‘‘G. Salvatore’’, Via S. Pansini 5, 80131 Naples, Italy;
E-Mail: defranci@unina.it (V.d.F.)
Abstract: RNA-based approaches are among the most promising strategies aimed at developing safer and more effective therapeutics. RNA therapeutics include small non-coding miRNAs, small interfering RNA, RNA aptamers and more recently small activating RNAs. However, major barriers exist to the use of RNAs as therapeutics as for example: resistance to nucleases present in biological fluids, chemical stability, need of specific cell targeted delivery and easy entry in the cell. Such issues have been addressed by several recent reports that show the possibility to introduce chemical modifications in small RNAs to stabilize the molecular conformation and increase of several folds integrity still preserving their functional activity.  Further, several aptamers have been developed as excellent candidates for the specific recognition of cell surface targets. In the recent few years by taking advantage of recent advances in small RNA field molecular bioconjugates have been designed that permit specific targeting and may act as cargoes for cell internalization of  small RNAs acting on gene expression that will be discussed in this Review.

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