Sweet insight: Discovery could speed drug development

 The surface of cells and many biologically active molecules are studded with sugar structures that are not used to store energy, but rather are involved in communication, immunity and inflammation. In a similar manner, sugars attached to drugs can enhance, change or neutralize their effects, says Jon Thorson, a professor of pharmaceutical sciences at the University of Wisconsin-Madison School of Pharmacy.

Thorson, an expert in the attachment and function of these sugars, says that understanding and controlling them has major potential for improving drugs, but that researchers have been stymied because many novel sugars are difficult to create and manipulate. "The chemistry of these sugars is difficult, so we have been working on methods to make it more user friendly," he says.

Now, in a study published online in Nature Chemical Biology on Aug. 21, Thorson, graduate student Richard Gantt and postdoctoral fellow Pauline Peltier-Pain have described a simple process to separate the sugars from a carrier molecule, then attach them to a drug or other chemical. The process also causes a color change only among those molecules that have accepted the sugar. The change in color should support a screening system that would easily select out transformed molecules for further testing. "One can put 1,000 drug varieties on a plate and tell by color how many of them have received the added sugar," Thorson says.

Attached sugars play a key role in pharmacy, says Thorson. Not only can they change the solubility of a compound, but "there are transporters in the body that specifically recognize certain sugars, and pharmaceutical companies have taken advantage of this to direct molecules toward specific tissue or cell types. If we can build a toolbox that allows us to make these molecules on demand, we can ask, 'What will sugar A do when it's attached to drug B?'"

And although the new study was focused more on an improved technique rather than the alteration of drugs, Thorson adds that it does describe the production of some "really interesting sugar-appended drugs: anti-virals, antibiotics, anti-cancer and anti-inflammatory drugs. Follow-up studies are currently under way to explore the potential of these analogs."

The new molecules included 11 variants of vancomycin, a powerful antibiotic, each distinguished by the nature and number of attached sugars.

The essence of the new process is its starting point: a molecule that changes the energy dynamics of the sugar-attachment reaction, Thorson says. "This is one of the first systematic studies of the equilibrium of the reaction, and it shows we can drive it forward or in reverse, depending on the molecule that we start with."

In a single test tube, the new technique is able to detach the sugar from its carrier and reattach it to the biological target molecule, Thorson says. "Sugars are involved a vast range of biology, but there are still many aspects that are not well understood about the impact of attaching and removing sugars, partly because of the difficulty of analyzing and accessing these species."

Making variants of potential and existing drugs is a standard practice for drug-makers, and a recently published study by Peltier-Pain and Thorson revealed that attaching a certain sugar to the anti-coagulant Warfarin destroys its anti-clotting ability. The transformed molecule, however, "suddenly becomes quite cytotoxic -- it kills cells," he says. "We don't know the mechanism, but there is some interest in using it to fight cancer because it seems to act specifically on certain cells."

Sugars are also attached to proteins, cell surfaces and many other locations in biology, Thorson says. "By simplifying the attachment, we are improving the pharmacologist's toolbox. This study provides access to new reagents and offers a very convenient screening for new catalysts and/or new drugs, and for other things we haven't yet thought of. We believe this is going to open up a lot of doors."

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by University of Wisconsin-Madison. The original article was written by David Tenenbaum.

Journal Reference:

Richard W Gantt, Pauline Peltier-Pain, William J Cournoyer, Jon S Thorson. Using simple donors to drive the equilibria of glycosyltransferase-catalyzed reactions. Nature Chemical Biology, 2011; DOI: 10.1038/nchembio.638

Scientists find easier, cheaper way to make a sought-after chemical modification to pharmaceuticals

Scientists at The Scripps Research Institute have devised a much easier technique for performing a chemical modification used widely in the synthesis of drugs and other products.

Known as "trifluoromethylation," the modification adds a CF3 molecule to the original compound, often making it more stable -- and, for a drug, keeping it in the body longer. With the new technique, chemists can perform this feat using a relatively simple, safe, room-temperature procedure and can even select the site of the modification on the target compound.

"I've been presenting this methodology at several pharma companies, and there's a lot of interest -- so much so that their chemists are starting to use it," said Scripps Research Professor Phil S. Baran, senior author of the new study, scheduled for publication the week of August 15, 2011, in an advance online edition of the Proceedings of the National Academy of Sciences.

Standard procedures for trifluoromethylation involve gases and associated hardware, high heat, metal catalysts, and oxidants. "The procedures are often prohibitively complicated, and medicinal chemists often don't have the time or the resources to get into it," said Baran.

Inspired by frequent consulting visits to pharmaceutical companies, Baran and his lab began to look for simpler ways to perform trifluoromethylation. After running more than 500 different reaction setups on a test compound, they found just one that delivered significant quantities of the desired reaction product. It was a simple setup that used a reagent known as sodium trifluoromethanesulfinate, an inexpensive chemical that is stable at room temperature.

Chemists had long believed that this reagent was unsuitable for trifluoromethylating a broad class of molecules frequently found in drug compounds, and also that the reagent required the use of catalyzing metal salts. But in this initial screening, the reagent, known as Langlois's reagent for its discoverer, the French chemist Bernard R. Langlois, seemed to work even without such constraints.

Baran and his team began collaborating with fellow Scripps Research chemistry Professor Donna Blackmond and members of her laboratory to study how Langlois's reagent works and to optimize its use, including the selection of trifluoromethylation sites on target compounds using certain solvents. With the optimized technique, they showed that they could directly and easily trifluoromethylate a variety of test compounds, including the natural malaria drug quinine and the synthetic anti-smoking drug varenicline (Chantix).

"The collaboration with Donna Blackmond and her lab was crucial in enabling us to improve the procedure and to understand why certain modifications led to those improvements," said Baran.

The new technique in principle makes it more feasible for pharmaceutical companies to modify and improve specific drug compounds of interest. It also means that these companies can expand the existing compound libraries they use for drug-discovery screening by making trifluoromethylated versions of these compounds quickly and easily.

"In one instance, a chemist at Pfizer told me that the trifluoromethylated compound we made in one step with our technique would have taken at least eight steps using standard techniques," said Baran.

The Baran and Blackmond labs are now working on new reagents that may be used in this reaction and ways to enable fine control of trifluoromethylation sites. "The interplay of the two labs at the nexus of synthesis and mechanistic analysis is driving this project forward in new and exciting directions," Baran said.

The two first authors of the paper, "Innate C-H Trifluoromethylation of Heterocycles," are Yining Ji and Tobias Brueckl of the Scripps Research Baran lab. Others who contributed are Ryan D. Baxter of the Scripps Research Blackmond lab and Yuta Fujiwara, Ian B. Seiple, and Shun Su of the Baran lab.

The work was supported in part by a grant from the National Institute of General Medical Sciences, part of the National Institutes of Health.

Story Source:

The above story is reprinted (with editorial adaptations ) from materials provided by The Scripps Research Institute.

Journal Reference:

Yining Ji, Tobias Brueckl, Ryan D. Baxter, Yuta Fujiwara, Ian B. Seiple, Shun Su, Donna G. Blackmond, Phil S. Baran. Innate C-H trifluoromethylation of heterocycles. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1109059108

Analytik Jena After Nine Months with Growth in Operating Business

 With sales growth of almost 7.0 % and an increase of nearly 6.0 % in operating earnings, Analytik Jena is now entering the final straight of the 2010/2011 financial year. After nine months the Group generated sales of EUR 63.6 m and operating income of EUR 3.4 m. This was announced by the manufacturer of analytical measuring technology, life science instruments and optoelectronics at the presentation of the quarterly and the 9-months-figures in Jena.

The Group’s growing positioning on global markets is reflected in the rise in international sales in the reporting period. In total, goods were exported for EUR 45.0 m (previous year: EUR 38.9 m). This corresponds to well over two thirds of total sales or an export rate of 70.6 % as against 65.3 % in the the previous year.

The core segment of Analytical Instrumentation again benefited from its strong market positioning in Asia and increased its sales as forecast. The division generated sales of EUR 40.1 m (previous year: EUR 35.9 m) or a sales increase of 11.9 %. In the Life Science segment the Group generated sales of EUR 20.0 m (previous year: EUR 20.3 m) and 1.5 % less income than in the same period of the previous year. This development is primarily due to the fact that the sales forecast were postponed to the fourth quarter of 2010/2011. The Optics division contributed EUR 3.5 m (previous year: EUR 3.4 m) to total consolidated sales after nine months.

Up 5.9 % year-on-year, the Group’s operating earnings development was solid. EBIT therefore amounted to EUR 3.4 m after the first nine months (previous year: EUR 3.2 m) with an EBIT margin of 5.4 %. EBITDA rose by 6.4 % to EUR 6.2 m (previous year: EUR 5.9 m). After the financial result had benefited from the favorable currency situation for Analytik Jena in the wake of rising financial income in the previous year, developments in foreign currencies, particularly the Japanese yen and the USD, had a negative effect this year due to higher financial expenses combined with lower financial income as against the same period of the previous year. Furthermore, earnings were significantly influenced by the measurement of derivatives compared to the previous year.

In the reporting period, Analytik Jena achieved a total net profit of EUR 0.6 m (previous year: EUR 2.5 m), 76.9 % less than in the previous year. This is equal to earnings per share of EUR 0.09 (previous year: EUR 0.47).

The Group’s total assets fell slightly by 3.2 % from EUR 83.6 m (September 30, 2010) to EUR 80.9 m as of June 30, 2011. In the reporting period, Analytik Jena reported equity of EUR 39.6 m (September 30, 2010: EUR 39.0 m). This corresponds to an equity ratio of 48.9 % (September 30, 2010: 46.7 %).
The Group’s cash and cash equivalents amounted to EUR 3.4 m as of the end of the reporting period.

As of June 30, 2011, the Group employed 803 staff, including 36 trainees (previous year: 780 employees, including 44 trainees).

Analytik Jena AG is retaining its forecasts for the 2010/2011 financial year and, in particular, is anticipating an increase in earnings in the fourth quarter, bringing it to its stated target for the year as a whole. The end of the financial year will be considerably influenced by the business recovery in Japan. All signals indicate that Analytik Jena on the basis of good incoming orders can significantly increase its sales as well. In the core business of Analytical Instrumentation the Company assumes a stable sales development. Specifically in the Life Science segment, the Company is forecasting a sound sales increase in the fourth quarter. The Optics consumer division will continue to recover until the end of the period.

"In light of the good sales and earnings development in the third quarter and on the basis of the continuing good incoming orders, we are assuming of achieving our demanding operating earnings target of EUR 4.5 m as of September 30, 2011", says Klaus Berka, CEO of Analytik Jena AG. "The biggest present risk for the Company is in currency effects. Regardless of this, we are predicting that the Company will enjoy a stable, positive performance overall in its last and, traditionally, strongest quarter. We are retaining our forecasts for the financial year."

 

Scientists copy the ways viruses deliver genes

Scientists at the National Physical Laboratory (NPL) have mimicked the ways viruses infect human cells and deliver their genetic material. The research hopes to apply the approach to gene therapy – a therapeutic strategy to correct defective genes such as those that cause cancer.

Gene therapy is still in its infancy, with obvious challenges around targeting damaged cells and creating corrective genes. An equally important challenge, addressed by this research, is finding ways to transport the corrective genes into the cell. This is a problem, because of the poor permeability of cell membranes.

This research describes a model peptide sequence, dubbed GeT (gene transporter), which wraps around genes, transports them through cell membranes and helps their escape from intracellular degradation traps. The process mimics the mechanisms viruses use to infect human cells.

GeT was designed to undergo differential membrane-induced folding - a process whereby the peptide changes its structure in response to only one type of membranes. This enables the peptide, and viruses, to carry genes into the cell. Interestingly, the property also makes it antibacterial and so capable of gene transfer even in bacteria-challenged environments.

To prove the concept, the researchers used GeT to transfer a synthetic gene encoding for a green fluorescent protein – a protein whose fluorescence in cells can be seen and monitored using fluorescence microscopy.

The design can serve as a potential template for non-viral delivery systems and specialist treatments of genetic disorders.

This research, performed at NPL, is a part of the NPL-led international research project 'Multiscale measurements in biophysical systems', which is jointly funded by NPL and the Scottish Universities Physics Alliance.

More information: The team's article GeT peptides: a single domain approach to gene delivery, detailing this research has just been published in Chem. Commun: http://pubs.rsc.or … C/c1cc13043a

Provided by National Physical Laboratory