09/2014
Discover this journal online at:
wileyonlinelibrary.com
ChemMedChem, European in origin but international in scope, deals with all aspects of drug discovery. It is co-owned by Chemistry Publishing Society Europe (ChemPubSoc Europe) and is published by Wiley-VCH. Contributions in ChemMedChem cover medicinal and pharmaceutical sciences, drug design, drug development and delivery, molecular modeling, combinatorial chemistry, target validation, lead generation, and ADMET studies, that is, research from the overlapping areas between biology, chemistry, and medicine. ChemMedChem publishes Communications and Full Papers, as well as Reviews, Minireviews, Highlights, Concepts, Essays, Book Reviews, and occasionally Conference Reports. Authors can submit manuscripts to ChemMedChem online through our homepage (see over) by clicking on “Submit an Article” and following the simple instructions. Most of the articles in this issue have already appeared online on wileyonlinelibrary.com. See www.chemmedchem.org under Early View
CHEMMEDCHEM EDITORIAL DOI: 10.1002/cmdc.201402321
Medicinal Chemistry Is in Our Genes Saskia Neubacher and Scott D. Williams*[a]
I
t’s little wonder that proteins are the targets of most drugs in use today. They are, after all, directly where the action is; they are the machinery behind cell migration, oxygen transport and the successful function of countless metabolic pathways. Their activities are carefully regulated at various well-characterized levels, and given the immense range of tertiary and quaternary protein structures, it makes perfect sense to develop therapies that take advantage of the specificity inherent to the protein world.
DNA and RNA, on the other hand, are still emerging as targetable biomolecules and therapeutic agents in their own right. Since the elucidation of its structure in the early 1950s, duplex DNA, with its simplicity, symmetry, stability and elegance, has been an inspiration for scientists, architects and ar[a] Dr. S. Neubacher, Dr. S. D. Williams ChemMedChem, Co-owned and supported by ChemPubSoc Europe Wiley-VCH, Boschstrasse 12, 69469 Weinheim (Germany) Homepage: www.chemmedchem.org E-mail: [email protected]
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
tists alike. In the early years of molecular biology it was thought that DNA, as the keeper of genetic information, should be static and stable. The traditional view of DNA is steeped in decades of terminology that reinforces its image of permanence: blueprint, template, information storage. RNA was also thought to be merely the conduit of genetic information from DNA to proteins. These labels are accurate, of course, but they fall short of painting the entire picture. The iconic DNA double helix has greater fluidity than most people realize, and RNA takes on many more forms than originally identified. Today we recognize both DNA and RNA as being much more susceptiThe iconic DNA ble to fluctuation than a 1980s double helix has molecular biology textbook might greater fluidity lead one to conclude. DNA is not than most people just a linear blueprint, and RNA realize, and RNA plays roles far beyond conveying takes on many that blueprint information to the more forms than manufacture of proteins. originally identified.
ChemMedChem 2014, 9, 1915 – 1916
1915
CHEMMEDCHEM EDITORIAL
Given its many forms, RNA provided an early illustration that the degree of versatility in sequence and structure of nucleic acids can rival that of proteins. Not long after the textbook model of translation was established (mRNA, rRNA, tRNA), amongst others, the discovery of RNA splicing in the 1970s and RNA interference in the 1990s led to the identification of other forms of RNA that have, for example, regulatory (miRNA, siRNA) or processing (snRNA, snoRNA) functions. This has naturally led to the use of synthetic RNAs (or RNA/DNA mimics) as RNA- and DNA-active agents themselves, especially for cases in which off-target effects and cell delivery are major challenges. Ongoing efforts are also aimed at developing small-molecule DNA is not just binders of oligonucleotides, but a linear blueprint, these have not yet reached the and RNA plays roles high level of specificity we are far beyond conveying accustomed to from the protein that blueprint world. The relatively young field information to the of epigenetics (see the recent manufacture of Epigenetics Special Issue) has proteins. also revealed how DNA can be targeted—directly or indirectly— to exploit the ways in which epigenetic pathways regulate gene expression.
Overview articles
This special issue contains an impressive collection of key medicinal chemistry research reports in targeting both RNA and DNA, and there are some excellent overview articles that summarize state-of-the-art research. The Minireview on page 2013 by Yu, Ding et al. discusses the latest in DNA-based imaging probes and drug carriers. On page 1932, Bhan and Mandal review the involvement of long noncoding RNAs in gene regulation, epigenetics, and human disease. In their Concept article on page 2021, Vogel and Stafforst discuss site-directed RNA editing as a method to study protein and RNA function. Ennifar, Tisn, and Micouin review recent achievements in developing RNA binders to interfere with the replication cycle of HIV (page 1982). Okamoto’s Review on page 1958 gives a detailed account of DNA–osmium complexes and their ability to react specifically with C5-methylated pyrimidines, expanding the ability to analyze epigenetic modifications. In their Viewpoint (page 2031), Filichev and co-workers describe how new helicase assays can boost the discovery of G-quadruplex-specific ligands in the pursuit of treating cancer and diseases linked to defective DNA repair.
www.chemmedchem.org search. To name just a few contributions, Monchaud and colleagues (page 2035) show that both DNA and RNA G-quadruplexes can be targeted by anticancer peptide nucleic acid (PNA)–porphyrin conjugates. The Full Paper on page 2178 by Gatto, Gçttlich et al. is also focused on cancer, discussing the DNA cleavage activity of bis-3-chloropiperidines as alkylating agents. In their Communication on page 2040, Seth and colleagues show how modified RNA antisense oligonucleotides were used to decrease the mRNA levels of two specific genes in mouse liver and muscle tissue. Crich et al. show how the 6’-hydroxy group in apramycin is crucial to the activity of this antibiotic (page 2074; also featured on this issue’s front cover). With the aim of helping to improve efficacy in siRNA-based therapies, Yang and co-workers reveal the detailed reasons behind asymmetry in RNase A digestion of siRNAs in their Full Paper on page 2111. Finally, Nizet, Tor et al. show a new way to combat resistant bacteria by targeting the A-site in bacterial rRNA (page 2164).
Medicinal chemistry excellence is in our DNA
With more than 30 contributions, this issue is a bit thicker than usual, and it could have been much thicker still: there were many excellent papers that arrived after the production deadline passed, so there will be a significant number of DNAand RNA-based medicinal chemistry reports in ChemMedChem’s pages over the next few months. Indeed, this flow should remain steady for a long time—well after the push from this special issue has subsided. The opportunities and developments in the field of nucleic acid based therapies are increasing, and this was evidenced by the overwhelming and enthusiastic response to the compilation of this special issue. We hope you enjoy reading it as much as we enjoyed putting it together.
Original research papers
T
he bulk of this issue consists of top-notch primary research papers that report the fruits of ongoing efforts in RNA/DNA re-
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scott D. Williams, Ph.D. Sr. Associate Editor
Saskia Neubacher, Ph.D. Associate Editor
ChemMedChem 2014, 9, 1915 – 1916
1916
Discover this journal online at:
wileyonlinelibrary.com
ChemMedChem, European in origin but international in scope, deals with all aspects of drug discovery. It is co-owned by Chemistry Publishing Society Europe (ChemPubSoc Europe) and is published by Wiley-VCH. Contributions in ChemMedChem cover medicinal and pharmaceutical sciences, drug design, drug development and delivery, molecular modeling, combinatorial chemistry, target validation, lead generation, and ADMET studies, that is, research from the overlapping areas between biology, chemistry, and medicine. ChemMedChem publishes Communications and Full Papers, as well as Reviews, Minireviews, Highlights, Concepts, Essays, Book Reviews, and occasionally Conference Reports. Authors can submit manuscripts to ChemMedChem online through our homepage (see over) by clicking on “Submit an Article” and following the simple instructions. Most of the articles in this issue have already appeared online on wileyonlinelibrary.com. See www.chemmedchem.org under Early View
CHEMMEDCHEM EDITORIAL DOI: 10.1002/cmdc.201402321
Medicinal Chemistry Is in Our Genes Saskia Neubacher and Scott D. Williams*[a]
I
t’s little wonder that proteins are the targets of most drugs in use today. They are, after all, directly where the action is; they are the machinery behind cell migration, oxygen transport and the successful function of countless metabolic pathways. Their activities are carefully regulated at various well-characterized levels, and given the immense range of tertiary and quaternary protein structures, it makes perfect sense to develop therapies that take advantage of the specificity inherent to the protein world.
DNA and RNA, on the other hand, are still emerging as targetable biomolecules and therapeutic agents in their own right. Since the elucidation of its structure in the early 1950s, duplex DNA, with its simplicity, symmetry, stability and elegance, has been an inspiration for scientists, architects and ar[a] Dr. S. Neubacher, Dr. S. D. Williams ChemMedChem, Co-owned and supported by ChemPubSoc Europe Wiley-VCH, Boschstrasse 12, 69469 Weinheim (Germany) Homepage: www.chemmedchem.org E-mail: [email protected]
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
tists alike. In the early years of molecular biology it was thought that DNA, as the keeper of genetic information, should be static and stable. The traditional view of DNA is steeped in decades of terminology that reinforces its image of permanence: blueprint, template, information storage. RNA was also thought to be merely the conduit of genetic information from DNA to proteins. These labels are accurate, of course, but they fall short of painting the entire picture. The iconic DNA double helix has greater fluidity than most people realize, and RNA takes on many more forms than originally identified. Today we recognize both DNA and RNA as being much more susceptiThe iconic DNA ble to fluctuation than a 1980s double helix has molecular biology textbook might greater fluidity lead one to conclude. DNA is not than most people just a linear blueprint, and RNA realize, and RNA plays roles far beyond conveying takes on many that blueprint information to the more forms than manufacture of proteins. originally identified.
ChemMedChem 2014, 9, 1915 – 1916
1915
CHEMMEDCHEM EDITORIAL
Given its many forms, RNA provided an early illustration that the degree of versatility in sequence and structure of nucleic acids can rival that of proteins. Not long after the textbook model of translation was established (mRNA, rRNA, tRNA), amongst others, the discovery of RNA splicing in the 1970s and RNA interference in the 1990s led to the identification of other forms of RNA that have, for example, regulatory (miRNA, siRNA) or processing (snRNA, snoRNA) functions. This has naturally led to the use of synthetic RNAs (or RNA/DNA mimics) as RNA- and DNA-active agents themselves, especially for cases in which off-target effects and cell delivery are major challenges. Ongoing efforts are also aimed at developing small-molecule DNA is not just binders of oligonucleotides, but a linear blueprint, these have not yet reached the and RNA plays roles high level of specificity we are far beyond conveying accustomed to from the protein that blueprint world. The relatively young field information to the of epigenetics (see the recent manufacture of Epigenetics Special Issue) has proteins. also revealed how DNA can be targeted—directly or indirectly— to exploit the ways in which epigenetic pathways regulate gene expression.
Overview articles
This special issue contains an impressive collection of key medicinal chemistry research reports in targeting both RNA and DNA, and there are some excellent overview articles that summarize state-of-the-art research. The Minireview on page 2013 by Yu, Ding et al. discusses the latest in DNA-based imaging probes and drug carriers. On page 1932, Bhan and Mandal review the involvement of long noncoding RNAs in gene regulation, epigenetics, and human disease. In their Concept article on page 2021, Vogel and Stafforst discuss site-directed RNA editing as a method to study protein and RNA function. Ennifar, Tisn, and Micouin review recent achievements in developing RNA binders to interfere with the replication cycle of HIV (page 1982). Okamoto’s Review on page 1958 gives a detailed account of DNA–osmium complexes and their ability to react specifically with C5-methylated pyrimidines, expanding the ability to analyze epigenetic modifications. In their Viewpoint (page 2031), Filichev and co-workers describe how new helicase assays can boost the discovery of G-quadruplex-specific ligands in the pursuit of treating cancer and diseases linked to defective DNA repair.
www.chemmedchem.org search. To name just a few contributions, Monchaud and colleagues (page 2035) show that both DNA and RNA G-quadruplexes can be targeted by anticancer peptide nucleic acid (PNA)–porphyrin conjugates. The Full Paper on page 2178 by Gatto, Gçttlich et al. is also focused on cancer, discussing the DNA cleavage activity of bis-3-chloropiperidines as alkylating agents. In their Communication on page 2040, Seth and colleagues show how modified RNA antisense oligonucleotides were used to decrease the mRNA levels of two specific genes in mouse liver and muscle tissue. Crich et al. show how the 6’-hydroxy group in apramycin is crucial to the activity of this antibiotic (page 2074; also featured on this issue’s front cover). With the aim of helping to improve efficacy in siRNA-based therapies, Yang and co-workers reveal the detailed reasons behind asymmetry in RNase A digestion of siRNAs in their Full Paper on page 2111. Finally, Nizet, Tor et al. show a new way to combat resistant bacteria by targeting the A-site in bacterial rRNA (page 2164).
Medicinal chemistry excellence is in our DNA
With more than 30 contributions, this issue is a bit thicker than usual, and it could have been much thicker still: there were many excellent papers that arrived after the production deadline passed, so there will be a significant number of DNAand RNA-based medicinal chemistry reports in ChemMedChem’s pages over the next few months. Indeed, this flow should remain steady for a long time—well after the push from this special issue has subsided. The opportunities and developments in the field of nucleic acid based therapies are increasing, and this was evidenced by the overwhelming and enthusiastic response to the compilation of this special issue. We hope you enjoy reading it as much as we enjoyed putting it together.
Original research papers
T
he bulk of this issue consists of top-notch primary research papers that report the fruits of ongoing efforts in RNA/DNA re-
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scott D. Williams, Ph.D. Sr. Associate Editor
Saskia Neubacher, Ph.D. Associate Editor
ChemMedChem 2014, 9, 1915 – 1916
1916
