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How Much Peptide Does it Take to Kill a Bacteria?

Posted on behalf of Dr Liana Allen, guest web writer for Organic & Biomolecular Chemistry.

Antibiotics are drug compounds used to treat infections caused by bacteria, such as tuberculosis and some forms of meningitis. The processes involved in bacteria cell reproduction are highly complicated and many different targets along the biological pathway of bacterial cell replication have been identified as potential opportunities to disrupt bacterial growth. Antibacterial drugs can be described as ‘bactericidal’ if they kill the bacterial cells by inhibition of bacteria cell wall or cell membrane synthesis, or by interfering with an essential bacterial enzyme. Those which target bacterial protein synthesis can be described as ‘bacteriostatic’ as they stop bacteria from reproducing but otherwise do not harm them.

One specific mode of antibacterial action is interaction with DNA gyrase, which is an enzyme involved in the unwinding of double stranded DNA helices during DNA replication.1 DNA gyrase is an enzyme which is not present in humans, making it an especially good target for antibiotics. One way in which antibacterial molecules interact with DNA gyrase is through stabilization of a DNA-gyrase covalent complex which is formed during the DNA replication process. The result of this interaction is the release of ‘broken DNA’, which kills the organism. For this reason, antibacterial agents which behave in this way are referred to as DNA gyrase poisons.

Microcin B17 (MccB17) structure

Microcin B17 (MccB17)

Microcin B17 (MccB17) is a peptide which displays antibacterial action and is thought to act as a DNA gyrase poison, but unfortunately, the full MccB17 peptide is not a suitable drug candidate due to its poor physiochemical properties. MccB17 is particularly interesting as the mature peptide contains some unusual hetrocyclic units.

In this paper, Katrina A. Jolliffe, Richard J. Payne and colleagues aimed to investigate the structure-activity relationship of MccB17 in order to determine exactly which parts of the peptide are needed for the antibacterial action and to develop a simplified DNA gyrase poison which would be a good lead candidate for antibacterial drug discovery. Using their own synthetic methodology,2 they prepared a range of full length and truncated analogues of MccB17, then tested their abilities to act as DNA gyrase poisons. They then compared the results with a known, potent DNA gyrase poison, ciprofloxacin. Many of the prepared analogues showed activity very similar to the native peptide; however some of the truncated variants actually performed better in this test. These promising results now enable more detailed investigation into the mechanism of bactericidal action of MccB17. In a second series of experiments, the peptides were tested for their antibacterial activity against two strains of E. coli. In this test it was the full length native MccB17 which gave the best results, suggesting that, even though truncated analogues can still exhibit DNA gyrase poisoning activity, the full length sequence would still currently be needed for bactericidal activity in vivo.

To read more, see;

Synthesis of Full Length and Truncated Microcin B17 Analogues as DNA Gyrase Poisons
R. E. Thompson, F. Collin, A. Maxwell, K. A. Jolliffe and R. J. Payne,
Organic & Biomolecular Chemistry, 2014, DOI: 10.1039/C3OB42516A.

Free to access until 7th March

References
1 Gore, J., Bryant, Z., Stone, M. D., Nöllmann, M., Cozzarelli, N.R., Bustamante, C. Nature, 2006, 439, 100.
2 Thompson, R. E., Jolliffe, K. A., Payne, R. J., Org. Lett., 2011, 13, 680.


Dr C. Liana AllenDr C. Liana Allen is currently a post-doctoral research associate in the group of Professor Scott Miller at Yale University, where she works on controlling the enantio- or regioselectivity of reactions using small peptide catalysts. Liana received her Ph.D. in organic chemistry at Bath University with Professor Jonathan Williams, where she worked on developing novel, efficient syntheses of amide bonds.

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Peptides Give a Free Ride Through the Membrane

Posted on behalf of Liana Allen, guest web writer for Organic & Biomolecular Chemistry  

All biological cells possess a cell membrane, which are lipid bilayers containing proteins embedded within them. One of the important properties of this membrane is its selective permeability to species such as small molecules and metal ions.1 This characteristic allows cell membranes to separate compounds with different chemical properties and act as a barrier to certain substances. While selective permeability is an essential function of cell membranes, it also leads to low efficiency of drug molecules which have low permeability through the membrane, yet need to enter the cells to be of therapeutic value. This is one of the reasons that the use of anti-cancer therapeutic agents is currently limited.2 

One strategy to overcome this problem is to use a cell-penetrating peptide (CPP) as a ‘transporter’ of drug molecules across the cell membrane to deliver treatments into the target cells. Such transporter peptides are usually short, cationic sequences, allowing them to bind to the negatively charged head groups of lipids in the membrane and subsequent entry into the cell. This strategy offers an opportunity to increase the bioavailability of drugs and thus lower the dosage required to achieve a significant effect.3 While CPPs increase the amount of drug which enters the cell, one problem with this method is a lack of selectivity between diseased cells and normal, healthy cells. One approach which has been taken to further improve the selective delivery of drugs into target cells is conjugating the CPP to another ‘homing’ peptide, one which binds selectively to receptors in human tumor cells. This allows drug delivery to specific cells, decreasing the side effects and toxicity to normal, healthy cells. 

In this paper, the authours search for a cell-penetrating peptide to be used as a transporter of drugs through the membrane of cancerous cells. Their search was based on a library of peptides which all displayed the desired characteristics of CPPs.4 After establishing which the most efficient membrane-permeating peptide in the library was, a three-component conjugate of the CPP, a homing peptide and a known cytotoxic, anti-cancer agent (chlorambucil) was synthesized and tested to assess its cellular uptake and cytotoxicity. The authours identified a peptide named ‘BP16’ as a potential new CPP with high cellular uptake, yet no cytotoxicity towards cancerous or healthy cells. Conjugating the cytotoxic agent chlorambucil to BP16 led to an impressive 6- to 9-fold increase in the drugs activity. When combined with a homing peptide, the drug activity was increased a further 2- to 4.5 times. These promising results show that BP16 is a suitable non-toxic delivery vector for the transport of drugs through cellular membranes. 

To read more, see; 

  

Identification of BP16 as a non-toxic cell-penetrating peptide with highly efficient drug delivery properties
Soler, M. González, D. Soriano-Castell, X. Ribas, M. Costas, F. Tebar, A. Massaguer, L. Feliu, M. Plantas,
Organic & Biomolecular Chemistry, 2014, DOI: 10.1039/C3OB42422G

Free to access until 7th February 

Structure of BP16 and confocal microscopy image showing BP16 (green) and cell nucleus (blue) after 180 mins incubation at 37 oC

Structure of BP16 and confocal microscopy image showing BP16 (green) and cell nucleus (blue) after 180 mins incubation at 37 oC

 

References 

1 A. Lehninger, Principles of Biochemistry, 2nd Ed. 2003, (Worth Publishers ed.).
2 E. Raschi, V. Vasina, M. G. Ursino, G. Boriani, A. Martoni, F. De Ponti, Pharmacol. Ther., 2010, 21, 389.
3
S. B. Fonseca, M. P. Pereira, S. O. Kelley, Adv. Drug. Deliv. Rev., 2009, 61, 953.
4 E. Badosa, R. Ferre, M. Planas, L. Feliu, E. Besalu, J. Cabrefiga, E. Bardaji, E. Montesinos, Peptides., 2007, 28, 2276. 


Dr C. Liana Allen is currently a post-doctoral research associate in the group of Professor Scott Miller at Yale University, where she works on controlling the enantio- or regioselectivity of reactions using small peptide catalysts. Liana received her Ph.D. in organic chemistry at Bath University with Professor Jonathan Williams, where she worked on developing novel, efficient syntheses of amide bonds.

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RSC Organic Division Poster Symposium 2013

RSC Organic Division Poster Symposium 2013The Organic Division once again hosted a very successful Poster Symposium on Monday 2nd December 2013, sponsored by F. Hoffmann La Roche Ltd. This year, 37 PhD students were invited to The Chemistry Centre to present their work to leading organic chemists in academia and industry. Many of the delegates commented on the high quality and exciting range of the chemistry on display, and the judges, Dr John Clough (Syngenta) and Prof. Alan Armstrong (Imperial College London) had a difficult time selecting the winners.

Nonetheless, they did make a decision, and the First Prize went to Francis Lister (University of Manchester, supervised by Jonathan Clayden) for his work on The Development of Screw-Sense Responsive Fluorescent Probes. The industrial delegates were once again asked to select an Industry prize winner, focusing on potential for industrial application.  The winner of the 2013 Industry prize was Neal Fazakerley, for his poster about Total Synthesis of (+)-Pleuromutilin and Biologically Active Analogues (University of Manchester, supervised by David Procter).

Two runner-up prizes were also awarded to Katrina Kramer (Queen Mary’s University London) and Edward Emmett (Oxford University). Finally, all the PhD students were asked to select their favourite poster, and the winner of this Participants’ Prize was Matthew Grayson from the University of Cambridge, supervised by Jonathan Goodman, for his poster – Combining Computational and Experimental Methods to Understand and Develop Asymmetric Methodology in Organic Chemistry

The Roysal Society of Chemistry  would like to acknowledge the support of many people, not least our many industrial sponsors. In addition we would like to thank the judges and the scientific committee for their hard work in making the event such a success. And finally, thank you to all the supervisors and research groups who continue to support this symposium, allowing us to showcase such a fantastic range of organic chemistry from around the UK every year.

Winners of the RSC Organic Division Poster Symposium 2013

Left to right: Andrew Thomas, Neal Fazakerley, Francis Lister, Matthew Grayson, Edward Emmett, Igor Larossa, John Clough, Alan Armstrong

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Introducing two new article types for Organic & Biomolecular Chemistry

OBC is introducing two new review article types: Reviews and Perspectives. These replace previous review article types and offer our authors and readers an even broader range of reviews, opinions and commentaries on the latest developments in organic chemistry and chemical biology.

Reviews
OBC Reviews are short, easy-to-read review articles covering current areas of interest to the OBC audience. Flexible in style, they give a concise and critical appraisal of recent advances in an established field or a new area of research.

Authors are encouraged to include their own views on developments, trends and future directions, with speculation about the future potential of the field particularly encouraged. Reviews are typically 6-12 pages in length. 

Reviews replace the previous Perspective and Emerging Area article types. While there is a change in name, the flexibility and breadth of style and content remain very much the same. Authors can write on established topics of current interest or emerging topics that are in the early stages of development. All of these styles will be consolidated under the Review name.*

Perspectives
OBC Perspectives are changing. These are now a new article style which will highlight pieces of exciting, recently-published research. Written by the authors of the original research, Perspectives will give a personal viewpoint on the topic, discussing their research in the wider context of the field and the future potential for the area.

Perspectives are designed to be short (2-4 printed pages) articles, briefly covering:

  • The background to the research area; its importance and previous developments
  • A summary of the key aspects of the research paper(s) recently published by the author
  • An outlook on future progression of the field, including how the author’s research could impact that

 Each Perspective will focus on just one or two recently-published research papers by the author. They will not cover large aspects of an author’s previous research.

 For guidelines on the new article types please click on the following links: Reviews | Perspectives.

*As a result of these changes the Emerging Area article type has been discontinued. Any emerging area style article should now be submitted under the Review article type.

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Mutant enzymes help break cocaine habit

An enzyme modified to hydrolyse cocaine 1000 faster than it did before could form the basis of the first medicinal treatment for cocaine addiction. Not only can the enzyme swiftly chop cocaine into inactive metabolites but modification of the enzyme has not affected its selectivity towards other natural substrates.

A treatment for cocaine abuse could be on the horizon © Shutterstock

A treatment for cocaine abuse could be on the horizon © Shutterstock

Cocaine is one the most widely used illegal drugs in the world. Unlike many other commonly abused substances, there are no proven medications available to treat cocaine addition. The health consequences of cocaine abuse are severe and addicts can cause significant societal problems. Finding an addiction treatment is therefore of the utmost importance.

Substrate selectivity of high-activity mutants of human butyrylcholinesterase
Chang-Guo Zhan et al.
Org. Biomol. Chem., 2013, Advance Article
DOI: 10.1039/C3OB41713A

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Antigenic sugars identified for Chagas disease

Scientists in the US and Spain have synthesised the combinations of sugars from the surface of the Chagas disease parasite that trigger the human immune response to it. This could help establish better diagnostic tests for the disease, and even a vaccine.

The triatomine beetles that transmit Chagas disease are known as kissing bugs because they tend to feed on people’s faces

The triatomine beetles that transmit Chagas disease are known as kissing bugs because they tend to feed on people’s faces

Chagas disease is caused by the parasite Trypanosoma cruzi. The parasite is transmitted by contaminated food, blood transfusions and blood sucking beetles commonly known as kissing bugs. After a phase of acute local infection, the disease becomes chronic and can eventually lead to life-threatening heart and digestive system disorders. Already endemic in Latin America, Chagas disease is also becoming more of a health issue in Europe and the US with blood banks now screening for it.

Currently, Chagas diagnosis involves spotting the parasite during microscopic investigation of blood samples or checking to see if antibodies in blood samples of infected patients bind to a lysate of Chagas parasites, but these tests are not very sensitive. As treatment is only effective at the acute stage of infection, better diagnostics are highly desirable.

The surface of the parasite is garnished with unusual sugars, but until now it has not been clear which ones elicit antibodies to the parasite. Sugar chemist Katja Michael and glycobiologist Igor Almeida from the University of Texas at El Paso and colleagues have synthesised combinations of α-galactose sugars from the Chagas parasites’ surface to solve the mystery. Sera of blood samples from infected patients were added to fluorescent immunoassays of the different sugar combinations. The assay revealed the disaccharide Galα(1,3)–Galβ as the immunodominant glycotope on the parasite’s cell surface.

Read the full article in Chemistry World

Potential use of synthetic α-galactosyl-containing glycotopes of the parasite Trypanosoma cruzi as diagnostic antigens for Chagas disease
R A Ashmus et al
Org. Biomol. Chem., 2013, Advance Article
DOI: 10.1039/C3OB40887F

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Mukaiyama Aldol Reaction – Join the 40th Anniversary Symposium

We are delighted to announce the Mukaiyama Aldol Reaction – 40th Anniversary Symposium which will take place on Saturday 31st August 2013 in Tokyo, Japan.

Key speakers include:

  • Prof. Ryoji Noyori (RIKEN, and Nagoya University)
  • Prof.  Masakatsu Shibasaki (Institute of Microbial Chemistry)
  • … and many more

For the full list of speakers and topics, please visit the dedicated website.

If you would like to register, please email the conference organisers with with your contact details, using the subject line: ‘Overseas Registration’

Don’t miss out! – Closing date for registrations is 31st July 2013

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RSC/BMOS Young Investigator Award – Closing date 15 July 2013

15th BMOSThe RSC is delighted to announce a fantastic opportunity for Early Career Researchers to attend the 15th Brazilian Meeting on Organic Synthesis (BMOS) taking place in Campos do Jordão, Brazil, 10-13 November 2013. The conferences combines plenary and invited lectures from distinguished leaders in the field to discuss modern aspects of the art of organic synthesis. The full programme and list of speakers can be viewed via the conference website.

The Organic Division of the RSC will allocate awards to allow four outstanding researchers (two from the UK and two from Latin America) to attend the conference. Applicants must be 40 years old or under on the closing date – 15 July 2013. The winner will be selected by a selection committee which will include members of the RSC Organic Division and BMOS Organising Committee. Winners will receive a free registration, a certificate, an invitation to deliver a flash presentation and a generous contribution towards travel and accommodation. For more information and to apply visit: http://rsc.li/bmos15

Applications should be sent to RSC Science by closing date 15 July 2013  with email subject RSC/BMOS Young Investigator Award

For any queries please contact science@rsc.org

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Chemical Biology and Medicinal: Synthesis of a selective inhibitor of a fucose binding bacterial lectin from Burkholderia ambifaria

Pathogen-associated lectins are considered to be attractive targets for the development of antiadhesive drugs. It is of great importance to design sugar-based derivatives able to selectively bind to specific pathogen-associated lectins with the aim of fighting bacterial infections without interfering with human lectins involved in physiological processes. 

Graphical Abstract

The stereoselective synthesis of the new fucose-based derivative 1, as the first example of glycomimetic selectively recognized by the fucose-binding lectin BambL from Burkholderia ambifaria is described.

Scientists in Italy report the first example of a synthetic ligand able to selectively bind, in the micromolar range, the pathogen-lectin BambL. BambL is a fucose-specific lectin from Burkholderia ambifaria, a bacterium member of the Burkholderia cepacia complex (BCC), a closely related group of Gram-negative bacteria responsible for cepacia syndrome in immunocompromised patients.

The fucose-based mimetic is therefore a promising candidate for the development of antibacterial agents against infection by B. ambifaria.

Synthesis of a selective inhibitor of a fucose binding bacterial lectin from Burkholderia ambifaria
Barbara Richichi, A Imberty, Emilie Gillon, Rosa Bosco, Ieva Sutkeviciute, Franck Fieschi and  Cristina Nativi  
Org. Biomol. Chem., 2013, Accepted Manuscript
DOI: 10.1039/C3OB40520F

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Bursary opportunity for final year PhD students and postdocs to attend the Sao Paulo Advanced School Bioorganic Chemistry

The RSC is delighted to announce a fantastic bursary opportunity for PhD students/post docs to attend the Advanced School Bioorganic Chemistry taking place in Araraquara, Brazil, 30 June – 05 July 2013. The school includes talks and discussion sessions from highly qualified scientists (including Professor Steven V. Ley from the University of Cambridge) and leaders in the field covering bioorganic chemistry, involving aspects of natural products, medicinal chemistry, synthesis and spectroscopic methods.  The full programme can be viewed here: http://www.bioorgchemespca.iq.unesp.br/nodes/view/program

FAPESP (Sao Paulo Research Foundation) have invited the RSC to select 2 UK students to participate in the meeting. The bursary will cover international and domestic transportation, hotel accommodation, meals, registration fee and welcome reception. To apply please complete the form which is available download here and at the end of this post. Return to science@rsc.org by 19 April 2013 at 4pm.

Sao Paulo Advanced School in Bioorganic Chemistry

Closing date for application is 4pm on 19 April 2013
 
For any queries please contact science@rsc.org

Application Form for the Advanced School Bioorganic Chemistry

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