Special Issue "G-Quadruplexes & i-Motif DNA"

Guest Editor
Prof. Dr. Edwin A. Lewis
Department of Chemistry, 1115 Hand Lab, Box 9573, Mississippi State, MS 39762, USA
Website: http://www.chemistry.msstate.edu/people/faculty/detail.php?faculty=lewis
E-Mail: ELewis@chemistry.msstate.edu
Phone: +1 662 325 3354
Fax: +1 662 325 1618
Interests: structure, stability, and drug binding properties of G-quadruplex and i-Motif DNA's; biological function of G-quadruplex and i-Motif forming sequences located in the regulatory regions of more than 40% of all human genes; drugability of G-quadruplex and i-Motif features found in the promoter regions of many oncogenes, e.g. c-MYC, Bcl-2, and K-ras; the use of thermodynamics for specific DNA-small molecule interactions in rational drug design

Dear Colleagues,

Guanine has long been known to self associate by π-π stacking or into G-tetrads stabilized by Hoogsteen H-bonds between N2 and N7, and N1 and O6 on adjacent guanines. Short G-rich DNA (or RNA) sequences can also form intermolecular G-quadruplexes containing from 1 to 4 DNA strands while longer G-rich sequences can fold back onto themselves forming intramolecular G-quadruplexes. It is now known that G-quadruplex forming sequences are found throughout the genome with more than 40% of all human genes having a potential G-quadruplex forming sequence located within 1 kb of the gene start site. Obviously, wherever there is a G-quadruplex forming sequence in one strand the complimentary strand contains a C-rich sequence capable of forming an i-motif. Even though G-quadruplexes have been studied for more than 20 years, the exact nature of their biological significance, other than in the single strand telomere overhang, is not well understood. It is commonly thought that G-quadruplexes and i-motif DNA must be important in gene regulation. For this reason, the G-quadruplex and i-motif structures represent attractive drug targets; small molecules that can stabilize these structures have been investigated as anti-cancer therapeutics. The stabilized higher order structures cannot bind to proteins required to form the transcriptionally active complex thereby down regulating the gene (or oncogene) having G-rich promoter sequences. Several proteins have been found that recognize quadruplex structure including loop bases and sequence. Other than their biological interest, the g-quadruplex and i-motif structures are gaining interest in the materials and nano-materials areas. G-quadruplex structure is known to be sensitive the stabilizing cation (e.g. Na+ vs. K+) while the i-motif structure is known to be sensitive to pH. These properties raise the possibility that sensors or switches could be fabricated using G-quadruplexes or i-motifs. The general focus of this special issue of Molecules will be to look at the structure, stability and ligand binding properties of G-quadruplexes and i-motifs, particularly from the standpoint of their biological activity or their materials properties.

Dr. Edwin A. Lewis
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. Molecules is an international peer-reviewed Open Access monthly 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 1800 CHF (Swiss Francs).

• G-quadruplex
• G-tetrad
• i-motif
• intercalative motif
• drug discovery/design
• ligand binding
• biomedical
• hoogsteen hydrogen bonding
• telomere
• gene regulation
• oncogenes
• materials
• nano-materials
• conformational switches
• supramolecular
• cancer

Type of Paper: Review
Title: G-quadruplex Structures in Human Genome as Novel Therapeutic Targets in Cancer
Authors: Graziella Cimino-Reale, Joanna Bidzinska, Nadia Zaffaroni and Marco Folini
Affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Amadeo, 42, 20133 Milano, Italy
Abstract: G-quadruplexes are secondary structures that may form within guanine-rich nucleic acid sequences. Telomeres have received much attention in this regard since they can fold into several distinct intramolecular G-quadruplexes, leading to the rational design and development of G-quadruplex stabilizing molecules. These ligands were shown to selectively exert an antiproliferative and chemosensitizing activity in in vitro and in vivo tumor models, without appreciably affecting normal cells. Such findings point to them as possible drug candidates for clinical applications. Other than in telomeres, G-quadruplexes may form at additional locations in the human genome, including gene promoters and untranslated regions. For instance, stabilization of G-quadruplex structures within the promoter of c-Myc, c-Kit, or KRAS resulted in an antitumor effect as a consequence of the specific down-regulation of the corresponding oncogene in selected experimental models. In addition, the alternative splicing of a number of genes may be affected for a therapeutic benefit through the stabilization of G-quadruplexes located within pre-mRNAs. It is now emerging that G-quadruplex structures may act as key regulators of several biological processes. Consequently, they are considered as attractive targets for broad-spectrum anticancer therapies, and much effort is being made to develop a variety of ligands with improved G-quadruplex recognition properties. Quarfloxin, a fluoroquinolone derivative designed to target a G-quadruplex within ribosomal DNA and disrupt protein-DNA interactions, has entered clinical trials for different malignancies. This review will provide some hints on the role of G-quadruplex structures in biological processes and will evaluate their implications as therapeutic targets.

Type Paper: Article
Title: DNA G-quadruplex-based Molecular Delivery System of Anticancer Agent in Response to Target mRNA
Authors: Hidenobu Yaku, Takashi Murashima, Daisuke Miyoshi and Naoki Sugimoto
Affiliations: Advanced Technology Research Laboratories, Panasonic Co., Ltd.
Frontier Institute for Biomolecular Engineering Research, Konan University
Faculty of Frontiers of Innovative Research in Science and Technology, Konan University,
Abstract: A G-quadruplex-based nanomachine, which can capture and release of a potent anticancer agent, copper(II) anionic phthalocyanine (CuAPC), in response to a target mRNA, is developed. The carrier G-quadruplex is designed to have a long loop, which is complementary to the target oligonucleotide. Since CuAPC can specifically bind to the G-quadruplex against duplex via π-π stacking interaction, unfolding of the G-quadruplex structure by the hybridization of the target oligonucleotide with its loop region should lead to release of the bound CuAPC. For the proof of the concept, G-quadruplexes with 10-30 mer loop, which can hybridize with a target sequence of the EGFR mRNA, were designed. Structural analysis showed that the designed G-quadruplexes form (3+1) or parallel conformations in the presence of 100 mM KCl and 10 mM MgCl2. By employing UV/vis and fluorescence titration experiments, it was found that the G-quadruplexes bind to CuAPC with Kd values of sub-micromolar or micromolar order, and that the G-quadruplexes bound with target RNAs with Kd values of around 10 nM. Furthermore, it was demonstrated that the target RNA allowed the release of CuAPC from the G-quadruplexes.

Type of Paper: Review
Title: High Pressure Effect on Thermal Stability of G-quadruplex DNA and Double Stranded DNA
Authors: Shuntaro Takahashi and Naoki Sugimoto
Affiliation: Frontier Institute for Biomolecular Engineering Research (FIBER), and Faculty of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
Abstract: Pressure is one of the thermodynamic parameters, and can induce structural changes according to the volumetric decrease. Although most proteins can denature triggered by pressure over 100 MPa due to the large cavities inside the molecules, a double stranded (ds) DNA rather is stabilized or destabilized very little depending on the sequence and salt conditions. However, the thermal stability of G-quadruplex DNA, which is one of the important non-canonical structures of nucleic acids for gene expressions in a cell, remarkably decreases with increasing pressure. The volumetric analysis determined that human telomeric DNA showed more than 50 cm3 mol-1 of volumetric change during transition of a coil to a quadruplex form. This value is approximately ten times larger than those of dsDNA in a physiological condition. The volumetric analysis also suggested that G-quadruplex DNA involves large amount of hydration change during the transition of coil to quadruplex. In fact, the presence of cosolute such as poly(ethylene glycol) largely repressed the pressure effect on the stability of G-quadruplex due to the alteration of circumstances of hydrating water. This review will provide the importance of gene expressions triggered by a local perturbation of pressure, and highlight the application of high-pressure chemistry in nucleic acids.