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Special Issue "Low Molecular Weight DNA and RNA Binding Agents"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry, Molecular and Cellular Biology".

Deadline for manuscript submissions: closed (30 July 2015)

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Special Issue Editor

Guest Editor

Prof. Dr. Eric C. Long

Department of Chemistry & Chemical Biology, Indiana University (IUPUI), 402 N. Blackford St., Indianapolis, IN, USA
Website | E-Mail
Interests: nucleic acid recognition and binding by low molecular weight antitumor agents, peptides, synthetic molecules, and metal complexes

Special Issue Information

Dear Colleagues,

Low molecular weight DNA and RNA binding agents function in some cases as drugs of established clinical importance and provide new chemical entities in the search for anti-cancer, anti-parasitic and anti-microbial therapeutics. In addition to their therapeutic relevance, low molecular weight agents that target DNA and RNA have the potential also to act as diagnostic tools and probes of nucleic acid structure and fundamental molecular recognition phenomena. Indeed, along with the canonical A- and B-form duplex structures formed by RNA and DNA biopolymers, agents that selectively interact with alternative three-dimensional nucleic acid structures, e.g., G-quadruplex structures, are of much current interest; such agents show promise towards understanding the biology of novel nucleic acid structures and, again, may have the potential to act as therapeutics. In all the above pursuits, the development and exploitation of rationally designed compounds, as well as species derived from natural product sources and metal complexes, continue to be investigated as sources of DNA and RNA binding low molecular weight agents. In addition, whole libraries of chemical agents targeted to nucleic acids are being designed and synthesized with increasing regularity necessitating the parallel development of strategies to select from among many compounds rapidly for particular nucleic acid binding properties. Thus, current research devoted to the study of low molecular weight DNA and RNA binding agents is multi-faceted and benefits from spanning multiple areas of science including, among others, the fields of chemistry, drug design, biology, toxicology, and biomedicine.

This special issue calls for original research, mini and full reviews, and perspectives that address the progress and current standing of the evolving field of low molecular weight DNA and RNA binding agents. The areas of interest for this special issue include, but are not limited to the fields keywords mentioned.

Prof. Dr. Eric C. Long
Guest Editor

Manuscript Submission Information

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. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences 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). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

metal complex – nucleic acid interactions
minor groove binding agents
alkylating agents
intercalators
clinically relevant agents
high-throughput screening assays
combinatorial or other library synthesis strategies
gene targeted agents
peptides and polyamides
non-canonical nucleic acid targets
DNA and RNA cleavage agents
structural investigations

Published Papers (7 papers)

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Research

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Open AccessArticle Cisplatin Targeting of Bacterial Ribosomal RNA Hairpins

by Gayani N. P. Dedduwa-Mudalige and Christine S. Chow

Int. J. Mol. Sci. 2015, 16(9), 21392-21409; doi:10.3390/ijms160921392

Received: 30 July 2015 / Revised: 26 August 2015 / Accepted: 29 August 2015 / Published: 7 September 2015

Cited by 7 | PDF Full-text (2159 KB) | HTML Full-text | XML Full-text

Abstract

[...] Read more.

Cisplatin is a clinically important chemotherapeutic agent known to target purine bases in nucleic acids. In addition to major deoxyribonucleic acid (DNA) intrastrand cross-links, cisplatin also forms stable adducts with many types of ribonucleic acid (RNA) including siRNA, spliceosomal RNAs, tRNA, and rRNA. All of these RNAs play vital roles in the cell, such as catalysis of protein synthesis by rRNA, and therefore serve as potential drug targets. This work focused on platination of two highly conserved RNA hairpins from E. coli ribosomes, namely pseudouridine-modified helix 69 from 23S rRNA and the 790 loop of helix 24 from 16S rRNA. RNase T1 probing, MALDI mass spectrometry, and dimethyl sulfate mapping revealed platination at GpG sites. Chemical probing results also showed platination-induced RNA structural changes. These findings reveal solvent and structural accessibility of sites within bacterial RNA secondary structures that are functionally significant and therefore viable targets for cisplatin as well as other classes of small molecules. Identifying target preferences at the nucleotide level, as well as determining cisplatin-induced RNA conformational changes, is important for the design of more potent drug molecules. Furthermore, the knowledge gained through studies of RNA-targeting by cisplatin is applicable to a broad range of organisms from bacteria to human. Full article

(This article belongs to the Special Issue Low Molecular Weight DNA and RNA Binding Agents)

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Open AccessArticle 2,6-Bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)pyridine and Its Benzene Analog as Nonmetallic Cleaving Agents of RNA Phosphodiester Linkages

by Luigi Lain, Salla Lahdenpohja, Harri Lönnberg and Tuomas Lönnberg

Int. J. Mol. Sci. 2015, 16(8), 17798-17811; doi:10.3390/ijms160817798

Received: 13 July 2015 / Revised: 13 July 2015 / Accepted: 28 July 2015 / Published: 3 August 2015

Cited by 1 | PDF Full-text (1652 KB) | HTML Full-text | XML Full-text | Supplementary Files

Abstract

[...] Read more.

2,6-Bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)pyridine (11a) and 1,3-bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)benzene (11b) have been shown to accelerate at 50 mmol·L⁻¹ concentration both the cleavage and mutual isomerization of uridylyl-3′,5′-uridine and uridylyl-2′,5′-uridine by up to two orders of magnitude. The catalytically active ionic forms are the tri- (in the case of 11b) tetra- and pentacations. The pyridine nitrogen is not critical for efficient catalysis, since the activity of 11b is even slightly higher than that of 11a. On the other hand, protonation of the pyridine nitrogen still makes 11a approximately four times more efficient as a catalyst, but only for the cleavage reaction. Interestingly, the respective reactions of adenylyl-3′,5′-adenosine were not accelerated, suggesting that the catalysis is base moiety selective. Full article

(This article belongs to the Special Issue Low Molecular Weight DNA and RNA Binding Agents)

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Open AccessArticle Synthesis, DNA Binding, and Antiproliferative Activity of Novel Acridine-Thiosemicarbazone Derivatives

by Sinara Mônica Vitalino de Almeida, Elizabeth Almeida Lafayette, Lúcia Patrícia Bezerra Gomes da Silva, Cézar Augusto da Cruz Amorim, Tiago Bento de Oliveira, Ana Lucia Tasca Gois Ruiz, João Ernesto de Carvalho, Ricardo Olímpio de Moura, Eduardo Isidoro Carneiro Beltrão, Maria do Carmo Alves de Lima and Luiz Bezerra de Carvalho Júnior

Int. J. Mol. Sci. 2015, 16(6), 13023-13042; doi:10.3390/ijms160613023

Received: 27 March 2015 / Revised: 27 May 2015 / Accepted: 29 May 2015 / Published: 9 June 2015

Cited by 13 | PDF Full-text (1818 KB) | HTML Full-text | XML Full-text | Supplementary Files

Abstract

[...] Read more.

In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide derivatives (3a–h) were synthesized, their antiproliferative activities were evaluated, and DNA binding properties were performed with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives. The calculated binding constants ranged from 1.74 × 10⁴ to 1.0 × 10⁶ M⁻¹ and quenching constants from −0.2 × 10⁴ to 2.18 × 10⁴ M⁻¹ indicating high affinity to ctDNA base pairs. The most efficient compound in binding to ctDNA in vitro was (Z)-2-(acridin-9-ylmethylene)-N- (4-chlorophenyl) hydrazinecarbothioamide (3f), while the most active compound in antiproliferative assay was (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide (3a). There was no correlation between DNA-binding and in vitro antiproliferative activity, but the results suggest that DNA binding can be involved in the biological activity mechanism. This study may guide the choice of the size and shape of the intercalating part of the ligand and the strategic selection of substituents that increase DNA-binding or antiproliferative properties. Full article

(This article belongs to the Special Issue Low Molecular Weight DNA and RNA Binding Agents)

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Open AccessArticle Efficient Synthesis of Peptide and Protein Functionalized Pyrrole-Imidazole Polyamides Using Native Chemical Ligation

by Brian M. G. Janssen, Sven P. F. I. van Ommeren and Maarten Merkx

Int. J. Mol. Sci. 2015, 16(6), 12631-12647; doi:10.3390/ijms160612631

Received: 24 March 2015 / Revised: 25 May 2015 / Accepted: 28 May 2015 / Published: 4 June 2015

Cited by 2 | PDF Full-text (2739 KB) | HTML Full-text | XML Full-text | Supplementary Files

Abstract

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The advancement of DNA-based bionanotechnology requires efficient strategies to functionalize DNA nanostructures in a specific manner with other biomolecules, most importantly peptides and proteins. Common DNA-functionalization methods rely on laborious and covalent conjugation between DNA and proteins or peptides. Pyrrole-imidazole (Py–Im) polyamides, based on natural minor groove DNA-binding small molecules, can bind to DNA in a sequence specific fashion. In this study, we explore the use of Py–Im polyamides for addressing proteins and peptides to DNA in a sequence specific and non-covalent manner. A generic synthetic approach based on native chemical ligation was established that allows efficient conjugation of both peptides and recombinant proteins to Py–Im polyamides. The effect of Py–Im polyamide conjugation on DNA binding was investigated by Surface Plasmon Resonance (SPR). Although the synthesis of different protein-Py–Im-polyamide conjugates was successful, attenuation of DNA affinity was observed, in particular for the protein-Py–Im-polyamide conjugates. The practical use of protein-Py–Im-polyamide conjugates for addressing DNA structures in an orthogonal but non-covalent manner, therefore, remains to be established. Full article

(This article belongs to the Special Issue Low Molecular Weight DNA and RNA Binding Agents)

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Review

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Open AccessReview Protein Recognition in Drug-Induced DNA Alkylation: When the Moonlight Protein GAPDH Meets S23906-1/DNA Minor Groove Adducts

by Gaëlle Savreux-Lenglet, Sabine Depauw and Marie-Hélène David-Cordonnier

Int. J. Mol. Sci. 2015, 16(11), 26555-26581; doi:10.3390/ijms161125971

Received: 5 August 2015 / Revised: 25 October 2015 / Accepted: 27 October 2015 / Published: 5 November 2015

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Abstract

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DNA alkylating drugs have been used in clinics for more than seventy years. The diversity of their mechanism of action (major/minor groove; mono-/bis-alkylation; intra-/inter-strand crosslinks; DNA stabilization/destabilization, etc.) has undoubtedly major consequences on the cellular response to treatment. The aim of this review is to highlight the variety of established protein recognition of DNA adducts to then particularly focus on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) function in DNA adduct interaction with illustration using original experiments performed with S23906-1/DNA adduct. The introduction of this review is a state of the art of protein/DNA adducts recognition, depending on the major or minor groove orientation of the DNA bonding as well as on the molecular consequences in terms of double-stranded DNA maintenance. It reviews the implication of proteins from both DNA repair, transcription, replication and chromatin maintenance in selective DNA adduct recognition. The main section of the manuscript is focusing on the implication of the moonlighting protein GAPDH in DNA adduct recognition with the model of the peculiar DNA minor groove alkylating and destabilizing drug S23906-1. The mechanism of action of S23906-1 alkylating drug and the large variety of GAPDH cellular functions are presented prior to focus on GAPDH direct binding to S23906-1 adducts. Full article

(This article belongs to the Special Issue Low Molecular Weight DNA and RNA Binding Agents)

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Open AccessReview May the Best Molecule Win: Competition ESI Mass Spectrometry

by Sarah Laughlin and W. David Wilson

Int. J. Mol. Sci. 2015, 16(10), 24506-24531; doi:10.3390/ijms161024506

Received: 28 August 2015 / Revised: 18 September 2015 / Accepted: 9 October 2015 / Published: 15 October 2015

Cited by 2 | PDF Full-text (2878 KB) | HTML Full-text | XML Full-text

Abstract

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Electrospray ionization mass spectrometry has become invaluable in the characterization of macromolecular biological systems such as nucleic acids and proteins. Recent advances in the field of mass spectrometry and the soft conditions characteristic of electrospray ionization allow for the investigation of non-covalent interactions among large biomolecules and ligands. Modulation of genetic processes through the use of small molecule inhibitors with the DNA minor groove is gaining attention as a potential therapeutic approach. In this review, we discuss the development of a competition method using electrospray ionization mass spectrometry to probe the interactions of multiple DNA sequences with libraries of minor groove binding molecules. Such an approach acts as a high-throughput screening method to determine important information including the stoichiometry, binding mode, cooperativity, and relative binding affinity. In addition to small molecule-DNA complexes, we highlight other applications in which competition mass spectrometry has been used. A competitive approach to simultaneously investigate complex interactions promises to be a powerful tool in the discovery of small molecule inhibitors with high specificity and for specific, important DNA sequences. Full article

(This article belongs to the Special Issue Low Molecular Weight DNA and RNA Binding Agents)

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Open AccessReview Interaction of DNA with Simple and Mixed Ligand Copper(II) Complexes of 1,10-Phenanthrolines as Studied by DNA-Fiber EPR Spectroscopy

by Makoto Chikira, Chew Hee Ng and Mallayan Palaniandavar

Int. J. Mol. Sci. 2015, 16(9), 22754-22780; doi:10.3390/ijms160922754

Received: 30 July 2015 / Revised: 30 August 2015 / Accepted: 9 September 2015 / Published: 21 September 2015

Cited by 7 | PDF Full-text (1309 KB) | HTML Full-text | XML Full-text | Supplementary Files

Abstract

[...] Read more.

The interaction of simple and ternary Cu(II) complexes of 1,10-phenanthrolines with DNA has been studied extensively because of their various interesting and important functions such as DNA cleavage activity, cytotoxicity towards cancer cells, and DNA based asymmetric catalysis. Such functions are closely related to the DNA binding modes of the complexes such as intercalation, groove binding, and electrostatic surface binding. A variety of spectroscopic methods have been used to study the DNA binding mode of the Cu(II) complexes. Of all these methods, DNA-fiber electron paramagnetic resonance (EPR) spectroscopy affords unique information on the DNA binding structures of the complexes. In this review we summarize the results of our DNA-fiber EPR studies on the DNA binding structure of the complexes and discuss them together with the data accumulated by using other measurements. Full article

(This article belongs to the Special Issue Low Molecular Weight DNA and RNA Binding Agents)

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