Archive for the ‘Chemical Biology’ Category
The 2015 Nobel Prize in Chemistry was jointly awarded to Tomas Lindahl, former director of Cancer Research UK’s Clare Hall Laboratories, Paul Modrich from Duke University in the US and Aziz Sancar from the University of North Carolina in the US for their “mechanistic studies of DNA repair”.
Tomas Lindahl, Paul Modrich and Aziz Sancar © Inserm-P. Latron, Mary Schwalm/AP/Press Association, Max Englund/UNC School of Medicine.
Tomas Lindahl’s research pieced together a molecular image of how base excision repairs DNA when a base of a nucleotide is damaged and subsequently managed to recreate the human repair process in vitro. The mechanism known as nucleotide excision repair, which excises damage from UV and carcinogenic substances, was then mapped by Aziz Sancar – the molecular details of this process changed the entire research field. Paul Modrich also studied the human version of the repair system. His work focused on DNA mismatch repair, a natural process which corrects mismatches that occur when DNA is copied during cell division.
The research carried out by the three 2015 Nobel Laureates in Chemistry has not only revolutionised our knowledge of how we function but also lead to the development of life – saving treatments. To celebrate these remarkable achievements, we are delighted to present a collection of recent Chemical Communications, Chemical Science and Chemical Society Reviews articles on DNA repair, FREE to read until 1 December 2015!
Finding needles in a basestack: recognition of mismatched base pairs in DNA by small molecules
Anton Granzhan, Naoko Kotera and Marie-Paule Teulade-Fichou
Chem. Soc. Rev., 2014, 43, 3630-3665
The chemical biology of sirtuins
Bing Chen, Wenwen Zang, Juan Wang, Yajun Huang, Yanhua He, Lingling Yan, Jiajia Liu and Weiping Zheng
Chem. Soc. Rev., 2015, 44, 5246-5264
Luminescent oligonucleotide-based detection of enzymes involved with DNA repair
Chung-Hang Leung, Hai-Jing Zhong, Hong-Zhang He, Lihua Lu, Daniel Shiu-Hin Chan and Dik-Lung Ma
Chem. Sci., 2013, 4, 3781-3795
A label-free and sensitive fluorescent method for the detection of uracil-DNA glycosylase activity
Jing Tao, Panshu Song, Yusuke Sato, Seiichi Nishizawa, Norio Teramae, Aijun Tong and Yu Xiang
Chem. Commun., 2015, 51, 929-932
DNA-mediated supercharged fluorescent protein/graphene oxide interaction for label-free fluorescence assay of base excision repair enzyme activity
Zhen Wang, Yong Li, Lijun Li, Daiqi Li, Yan Huang, Zhou Nie and Shouzhuo Yao
Chem. Commun., 2015, 51, 13373-13376
A fluorescent G-quadruplex probe for the assay of base excision repair enzyme activity
Chang Yeol Lee, Ki Soo Park and Hyun Gyu Park
Chem. Commun., 2015, 51, 13744-13747
A chemical probe targets DNA 5-formylcytosine sites and inhibits TDG excision, polymerases bypass, and gene expression
Liang Xu, Ying-Chu Chen, Satoshi Nakajima, Jenny Chong, Lanfeng Wang, Li Lan, Chao Zhang and Dong Wang
Chem. Sci., 2014, 5, 567-574
Sensitive detection of polynucleotide kinase using rolling circle amplification-induced chemiluminescence
Wei Tang, Guichi Zhu and Chun-yang Zhang
Chem. Commun., 2014, 50, 4733-4735
Rescuing DNA repair activity by rewiring the H-atom transfer pathway in the radical SAM enzyme, spore photoproduct lyase
Alhosna Benjdia, Korbinian Heil, Andreas Winkler, Thomas Carell and Ilme Schlichting
Chem. Commun., 2014, 50, 14201-14204
Expanding DNAzyme functionality through enzyme cascades with applications in single nucleotide repair and tunable DNA-directedassembly of nanomaterials
Yu Xiang, Zidong Wang, Hang Xing and Yi Lu
Chem. Sci., 2013, 4, 398-404
Detection of base excision repair enzyme activity using a luminescent G-quadruplex selective switch-on probe
Ka-Ho Leung, Hong-Zhang He, Victor Pui-Yan Ma, Hai-Jing Zhong, Daniel Shiu-Hin Chan, Jun Zhou, Jean-Louis Mergny, Chung-Hang Leung and Dik-Lung Ma
Chem. Commun., 2013, 49, 5630-5632
Endonuclease IV discriminates mismatches next to the apurinic/apyrimidinic site in DNA strands: constructing DNA sensing platforms with extremely high selectivity
Xianjin Xiao, Yang Liu and Meiping Zhao
Chem. Commun., 2013, 49, 2819-2821
The synthesis of tailor-made peptide chains represents a powerful tool for tuning the structure and properties of peptides, allowing for the development of analogues for medical, technological and synthetic purposes.
For example, the β-peptide is a synthetic peptide, which, in contrast to its naturally-occurring α-peptide analogue, is bonded through the β-carbon rather than the α-carbon. As a result of this seemingly small structural change, alterations in the peptide’s secondary structure and thermodynamic stability are observed.
Adding fluoride groups to peptide chains represents another way to alter and stabilise the folding structure through the presence of stronger hydrogen bonds and the introduction of fluorophilicity. This approach is generally employed for the addition of fluoride groups at ‘remote positions,’ spaced two or more methylene units from the peptide backbone. However, this method has less of an effect on the conformation of the peptide itself, and instead primarily influences the tertiary and quaternary self-aggregation of peptide chains, as a result of the fluorophilic effect of the functionalised peptide chains.
Much less commonly studied is the effect of incorporating fluorine groups in ‘direct proximity’ to the peptide chain, that is, directly attached to the β-carbon, where it is proposed that the intramolecular hydrogen bonding will be directly affected, and consequently, so too will the secondary structure of the peptide chain.
Yasuhiro Ishida and co-workers from the RIKEN Center for Emergent Matter Science have shown that this ‘direct’ fluorination of β-peptides can, in fact, affect the higher order structures of these peptide chains. Specifically, a hexameric β-peptide was designed, which consisted of cyclohexane-based β-amino acids in the 1-,3-,4- and 6-positions and L-alanine derivatives in the 2- and 5-positions, where the L-alanine methyl groups were either native or perfluorinated.
Irrespective of the degree of perfluorination in the β-peptide, it was found that the chains were arranged in the same left-handed 14-helix structure, with the NH-amide of the second and fifth residues participating in stabilising intramolecular H-bonding interactions. Moreover, it was found that although the presence of fluoride groups did not noticeably alter the overall secondary structure of the β-peptide chains, the stability of these structures was dramatically enhanced, showing the significant effect that fluoride groups can have on the hydrogen-bond donating ability of NH-amides.
This new approach of modifying peptide chains offers an interesting method for influencing the secondary, and higher order, structures of the compounds, as well as their kinetic and thermodynamic properties. The effect of these structural modifications offers the possibility of tuning the chemical and biological properties of these peptide chains for use in new types of antibiotics and synthetic systems.
Read this HOT ChemComm article in full!
Stabilization of β-peptide helices by direct attachment of trifluoromethyl groups to peptide backbones
Joonil Cho, Kyohei Sawaki, Shinya Hanashima, Yoshiki Yamaguchi, Motoo Shiro, Kazuhiko Saigo and Yasuhiro Ishida
Chem. Commun., 2014, 50, 9855–9858.
About the Writer
Anthea Blackburn is a guest web writer for Chemical Communications. Anthea is a graduate student hailing from New Zealand, studying at Northwestern University in the US under the tutelage of Prof. Fraser Stoddart (a Scot), where she is exploiting supramolecular chemistry to develop multidimensional systems and study the emergent properties that arise in these superstructures. When time and money allow, she is ambitiously attempting to visit all 50 US states before graduation.
What can cause a mutation in DNA? Well, if you were to ask the Incredible Hulk (nicely), he would probably say– well not a lot, he’s more of a doer, but Bruce Banner might tell you gamma rays. But that is so 20th century.
In a Communication recently published in ChemComm, José Pedro Pedro Cerón-Carrasco (Université de Nantes) and Denis Jacquemin (Institut Universitaire de France) have shown that DNA can mutate permanently if an appropriate external electric field is applied.
Application of the right level of electric field can lead to proton transfer, which can cause the formation of tautomers, i.e. isomers of the DNA bases. By interfering with the bases and their interaction, a mismatch or mutation can be induced.
Cerón-Carrasco and Jacquemin used a computational model to assess the effects of both positive and negative external electric fields on a DNA model to achieve an in vivo-like outcome. When applying an increasing strength of negative electric fields, they saw the more acidic H1 proton shift to the other base; intense positive fields activated the H2 proton.
The authors conclude that intense electric fields might damage DNA in a partially controlled way. This could have exciting applications for biochemistry or medicine– for example, selectively mutating a disease-causing cell. Or maybe, bestowing me with superpowers…
Interested in more? Read this HOT ChemComm article in full!
Electric field induced DNA damage: an open door for selective mutations
José Pedro Pedro Cerón-Carrasco and Denis Jacquemin
Chem. Commun., 2013, Accepted Manuscript
Sarah Brown is a guest web-writer for Chemical Communications. Sarah hung up her lab coat after finishing her PhD and post-doctorate in nanotechnology for diagnostics and therapeutics to become an assistant editor at the BMJ Publishing Group. When not trying to explain science through ridiculous analogies, you can often find her crocheting, baking and climbing, but not all at once.
Scientists, led by Renato Zenobi of the Swiss Federal Institute of Technology (ETH) in Zurich, have been investigating metabolites in exhaled breath, showing that each person’s breath holds a unique, characteristic molecular ‘breathprint,’ as recently featured on the BBC website. This means that high-precision chemical analysis of a patient’s breath can potentially provide an instant, pain-free and non-invasive medical diagnosis, and may even provide an early warning for healthy persons at risk for certain diseases. In the future, it may also be used to calculate safe dosages of anaesthesia tailored to each patient’s metabolism and tolerance, or as a fast and convenient doping check for athletes.
Using mass spectrometry, Zenobi and his team regularly measured and analysed the exhaled breath of eleven volunteers for eleven days, finding that each individual’s metabolic ‘breathprint’ showed a unique core pattern and remained stable enough to be useful for medical purposes. Their mass spectra of exhaled breath have shown peaks or signals representing around a hundred compounds, most of which they are just beginning to identify and assign.
Their findings represent a significant step towards ‘personalised medicine,’ and show great potential for other applications, such as in forensics or metabolomics.
Zenobi and his co-workers first published their early work in chemical breath analysis in a 2011 ChemComm article, in which they used their novel method to identify valproic acid, a medication for epilepsy, in exhaled breath.
Read the ChemComm article where it all began!
Real-time, in vivo monitoring and pharmacokinetics of valproic acid via a novel biomarker in exhaled breath
Gerardo Gamez, Liang Zhu, Andreas Disko, Huanwen Chen, Vladimir Azov, Konstantin Chingin, Günter Krämer and Renato Zenobi
Chem. Commun., 2011, 47, 4884-4886
Until now, drugs which fight gastrointestinal infections and those which treat acute inflammation have been found to interfere with each other. For instance, people infected with the Helicobacter pylori bacterium have needed to deal with the additional risk of gastrointestinal bleeding associated with the use of aspirin and other inflammatory drugs.
Australian research chemists, led by Philip C. Andrews of Monash University, have designed a new drug which treats gastrointestinal infections and acute inflammation at the same time. They have successfully synthesized bispirin, a bismuth acetylsalicylate complex which combines the effectiveness of bismuth carboxylate compounds as anti-infection agents with that of acetylsalicylic acid (aspirin) as an anti-inflammatory drug. Their initial tests have shown that bispirin’s antibacterial effects are comparable or better than those of current bismuth drugs, and investigations of bispirin’s anti-inflammatory activity are currently in progress.
This journal article has also been recently featured on C&EN – read it here.
Read this ‘HOT’ ChemComm article in full:
While current cancer-diagnosis methods rely on an invasive biopsy or the detection of cancer-specific biomarkers, South Korean scientists have developed a simple and non-invasive detector for cancer cells that could speed up the early diagnosis of the condition, leading to a greater chance of survival for cancer patients.
Cancer cells have been found to differ from normal cells in several ways, including the make up of their cell membranes. Cancer-cell membranes have been found to contain more anionic lipids than normal cells, leading to an overall negatively charged cell surface. Yoon-Bo Shim and co-workers from Pusan National University, have exploited this negative surface charge to develop a probe based on daunomycin, an anti-cancer drug that is known to interact strongly with anionic lipids.
Read the full article in Chemistry World.
Read the original journal article:
Cancer cell detection based on the interaction between an anticancer drug and cell membrane components
Chem. Commun., 2013, 49, 1900-1902
A novel cancer cell detection method, based on the interaction between daunomycin (DAN – an anticancer drug used in chemotherapy) and cell membrane components, has been developed by scientists in South Korea.
The method uses the electrochemical and fluorescence behaviour of DAN and uses an aptamer probe immobilised on a conducting polymer-gold nanoparticle composite film.
he aptamer sensor probes using electrochemical impedance spectroscopy and fluorescence microscopy. The method differentiates between cancerous and non-cancerous cells at low concentrations (0.01μM).
Read the ‘HOT’ Communication in full:
Cancer cell detection based on the interaction between an anticancer drug and cell membrane components
Pranjal Chandra , Hui-Bog Noh and Yoon-Bo Shim
Chem. Commun., 2013, DOI: 10.1039/C2CC38235K
Alzheimer’s disease is the most common form of dementia and, as there is no cure, early diagnosis is crucial for treatment to be effective. To this end, UK and US scientists have developed a labelled tracer compound that binds to plaques closely associated with Alzheimer’s disease (AD) so that the plaques can be picked up by a medical imaging technique.
The tracer compound is a [18F]-labelled barbiturate and is used with the imaging technique positron emission tomography (PET). Although other radiolabelled compounds have been used as PET tracers, using [18F]-labelled barbiturates for molecular imaging in AD has distinct advantages, such as good blood-brain barrier crossing ability, metabolic stability and easy accessibility.
As Alzheimer’s disease advances, symptoms can include confusion, irritability and aggression, and long-term memory loss © Shutterstock
Matteo Zanda at the University of Aberdeen and colleagues, in conjunction with Pfizer in the US, developed several fluorinated barbiturate analogues. The key to developing an effective molecular imaging radiotracer is the ability to distinguish between a healthy individual and someone suffering from a neurological disease, such as AD, they say. Barbiturates have a strong capacity for forming structures with biopolymers and are effective metal ion chelators. As such, the team thought that they would bind to AD-related plaques, which consist of the biopolymer β-amyloid and metal cations, such as Zn(II) and Cu(II).
See the Chemistry World story in full or read the Chem Comm article:
18 F-barbiturates are PET tracers with diagnostic potential in Alzheimer’s disease
Elisa Calamai , Sergio Dall’Angelo , David Koss , Juozas Domarkas , Timothy J. McCarthy , Marco Mingarelli , Gernot Riedel , Lutz F. Schweiger , Andy Welch , Bettina Platt and Matteo Zanda
Chem. Commun., 2013,49, 792-794
28 January 2013
Chemistry Centre, Burlington House, London
The therapeutic promise of regenerative medicine, as a way to restore aging or damaged tissues and organs, is one of the most exciting areas of medicines research. With the proportion of older people increasing, degenerative and chronic diseases are a major challenge. To move forward, the chemical sciences have a vital role to play in understanding
- disease mechanisms
- signalling of stem cells
- cellular differentiation
- new methodologies for surface modification
The 2013 Spinks Symposium will explore the critical issues that underpin developments in regenerative medicine and provide a clear understanding of the challenges involved in translating research outputs into application. Particular emphasis will be put on how medicinal chemistry/chemical biology research might provide a springboard to therapeutic development. Researchers from industry, academia and the wider health sciences sectors will join together for this stimulating workshop, including oral presentations discussion groups, flash presentations and a comprehensive poster session.
How can I get involved?
- Abstracts for the poster programme are now invited. Take full advantage of this exceptional opportunity to present your work and submit before Friday 21st December.
- Registration is also open and if you would like to benefit from the early bird rates be sure to secure your place before Friday 21st December