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Low Molecular Weight DNA and RNA Binding Agents

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

Deadline for manuscript submissions: closed (30 July 2015) | Viewed by 58370

Special Issue Editor

Department of Chemistry & Chemical Biology, Indiana University (IUPUI), 402 N. Blackford St., Indianapolis, IN, USA
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

Prof. Dr. Eric C. Long

Manuscript Submission Information

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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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2159 KiB  
Article
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; https://doi.org/10.3390/ijms160921392 - 07 Sep 2015
Cited by 17 | Viewed by 8638
Abstract
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. [...] 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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1652 KiB  
Article
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; https://doi.org/10.3390/ijms160817798 - 03 Aug 2015
Cited by 4 | Viewed by 4980
Abstract
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 [...] 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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1818 KiB  
Article
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; https://doi.org/10.3390/ijms160613023 - 09 Jun 2015
Cited by 79 | Viewed by 10268
Abstract
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 (3ah) were synthesized, their antiproliferative activities were evaluated, and DNA binding [...] 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 (3ah) 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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2739 KiB  
Article
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; https://doi.org/10.3390/ijms160612631 - 04 Jun 2015
Cited by 5 | Viewed by 7490
Abstract
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 [...] Read more.
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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4637 KiB  
Review
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; https://doi.org/10.3390/ijms161125971 - 05 Nov 2015
Cited by 12 | Viewed by 9804
Abstract
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 [...] Read more.
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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2878 KiB  
Review
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; https://doi.org/10.3390/ijms161024506 - 15 Oct 2015
Cited by 11 | Viewed by 7347
Abstract
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 [...] Read more.
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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1309 KiB  
Review
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; https://doi.org/10.3390/ijms160922754 - 21 Sep 2015
Cited by 44 | Viewed by 9103
Abstract
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 [...] 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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