Archive for the ‘Chemical Biology’ Category

Inducing β-Peptide Structures from the Inside Out

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.

 

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Superpowers ahoy! Electric field causes DNA mutations

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.

Turn the power up a little more and soon I will become Science Girl!: The DNA tautomers form under the influence of an external electric field. Circles indicate the protons that have been shifted compared to the canonical structure: H1 in blue and H2 in red.

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
DOI: 10.1039/C3CC42593B

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.


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‘Breathprint’ analysis as a real-time, non-invasive diagnostic tool

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.

C1CC10343A

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
DOI: 10.1039/C1CC10343A

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Making Bispirin: A new drug to fight both indigestion and pain

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.

Making Bispirin_graphical abstract

This journal article has also been recently featured on C&ENread it here.

Read this ‘HOT’ ChemComm article in full:

Philip C. Andrews, Victoria L. Blair, Richard L. Ferrero, Peter C. Junk and Ish Kumar
Chem. Commun., 2013, 49, 2870-2872
DOI: 10.1039/C3CC40645H

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A new system for cancer detection

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 fluorescing

Daunomycin interacting cancer cells viewed with fluorescene microscopy

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
DOI: 10.1039/C2CC38235K

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A new way to look at cancer cell detection

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

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Early Alzheimer’s diagnosis compound

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.

Tree that looks like a face with some leaves blowing away to represent memory loss in Alzheimer's diseaseAs 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
DOI: 10.1039/C2CC38443D

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Spinks Symposium 2013: Regenerative Medicine – registration open

 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
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Drug delivery: implications of gold-protein interactions

Researchers in Italy have shown that medicinal gold compounds interact strongly with the proteins of the copper trafficking system, which could have implications for drug delivery.

The copper trafficking system consists of proteins that help the uptake of copper into cells and then promote its transfer and delivery to copper-dependent cellular proteins.  One of these ‘chaperones’ is known as Atox-1.

Copper trafficking within a mammalian cell

Previous work has shown that platinum-based anticancer drugs strongly interact with copper trafficking system proteins and Messori and co-workers hypothesised that medicinal gold compounds might also do the same, especially in the +1 oxidation state; soft lewis acids, such as gold (I) ions react eagerly with Atox-1.

The interactions of three gold (III) compounds with Atox-1 were analysed through ESI-MS and revealed the formation of metal-protein adducts. The same major adduct was invariantly formed, matching the protein binding of a single gold (I) ion. Formation of this adduct implied that the gold (III) complex had broken down, a loss of ligands and reduction to a gold (I) species. ESI-MS also displayed peaks that corresponded to protein binding with two gold (I) ions. A stability study showed that one of the three gold-protein adducts was stable over 72 hours.

From their findings, the authors conclude that the cytotoxic gold compounds investigated form stable adducts with copper chaperone, Atox-1. These results have implications for medicinal drug design and our little friend, Atox-1 stays in a job.

Read this HOT Chem Comm article today (free to access until the 14th of December 2012):

Medicinal gold compounds form tight adducts with the copper chaperone Atox-1: biological and pharmacological implications
Chiara Gabbiani, Federica Scaletti, Lara Massai, Elena Michelucci, Maria A. Cinellu and Luigi Messori
Chem. Commun., 2012, 48, 11623-11625

Published on behalf of Sarah Brown, Chemical Communications web science writer.

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Origami, without the papercut, visualised

Researchers in China have been able to visualize the intracellular location of DNA origami with a label-free fluorescent probe.

But let’s unfold a few things first and figure out what that means. DNA origami is the folding of a strand of DNA to make arbitrary 2 or 3 dimensional shapes; this serves as a ‘scaffold’ for shorter DNA strands that help hold the structure in its folded shape. These structures may be used for drug delivery, biosensors and more. I once made an origami frog; I wonder if there are any similarities…

Direct visualisation of the distribution and stability of DNA origami in live, cellular systems has not been achieved. Fluorescent labels can be attached to DNA strands but these have their drawbacks, such as weak emission intensity, photobleaching and expensive. Ding and co-workers looked at alternatives to visualize DNA origami in live cells.

The group were inspired by research on a series of carbazole-based cyanine fluorescence probes, which have a weak emission when they are monomolecularly dissolved but switch to a strong luminescent state upon binding to DNA or protein molecules.  The significant enhancement is attributed to restricted intramolecular rotational (RIR) motions by anchoring the DNA molecules, which causes the large reduction in the non-radiative decay of fluorescence molecules.

DNA-origami visualised in cells

Follow the instructions (a) and you too won’t make DNA-origami visualised in cells (b)

Ding and co-workers then took some tubular DNA origami, the cyanine fluorophore and found that the carbazole-based cyanine molecules could be used as a sensitive optical switch, turned on when DNA origami is detected and turned off when the nanostructure degrades. After incorporating the cyanine probe molecules, the DNA origami-probe complex was administered to live cells. Excitingly, the green-yellow frog… erm, I mean, fluorescence was visible inside the cells treated with the probe. The group went further to try and understand the internalization mechanism of the DNA origami and found the probe localized in lysosomes. Finally, degradation studies showed that most DNA origami were dissociated after 60 hours, also a bit like my origami frog.

Unlike my attempts at origami, Ding and co-workers have demonstrated an exciting step in scaffolded DNA origami and its future applications in nanomedicine.

Read this HOT Chem Comm article today (free to access until the  5th of December 2012):

Visualization of the intracellular location and stability of DNA origami with a label-free fluorescent probe
Xibo Shen, Qiao Jiang, Jinye Wang, Luru Dai, Guozhang Zou, Zhen-Gang Wang, Wei-Qiang Chen, Wei Jiang and Baoquan Ding
Chem. Commun., 2012, 48, 11301-11303

Published on behalf of Sarah Brown, Chemical Communications web science writer.

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