The surface of cells and several biologically active molecules are dotted with sugar structures that instead of storing energy are involved in communication, immunity and inflammation. Similarly, sugars attached to drugs can increase, change or neutralize their effects. Jon Thorson, a professor of pharmaceutical sciences at the University of Wisconsin-Madison School of Pharmacy explained. On Aug. 21, the investigation was published online in Nature Chemical Biology.
According to Thorson, a professional in the attachment and function of these sugars, understanding and controlling them has huge potential for improving medications. As several new sugars are hard to create and manipulate, investigators have become frustrated. Thorson says, “The chemistry of these sugars is difficult, so we have been working on methods to make it more user friendly.”
Thorson, graduate student Richard Gantt and postdoctoral fellow Pauline Peltier-Pain, have described an easy method to separate the sugars from a carrier molecule, then attach them to a drug or other chemical. Only among those molecules that have accepted the sugar, the method triggers a change of color. This color change should help a screening system to easily select out transformed moleules for further testing. Therson states, “one can put 1,000 drug varieties on a plate and tell by color how many of them have received the added sugar.”
Attached sugars play a crucial role in pharmacy, not only can they change the solubility of a compound, he says, 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?'”
Even though the new investigation concentrated more on an improved method instead of the alteration of drugs, it does explain the production of a few really interesting sugar-appended drugs: anti-virals, antibiotics, anti-cancer and anti-inflammatory medications. Currently under way are follow-up investigations to discover the potential of these analogs.
11 variants of vancomycin, a powerful antibiotic, each distinguished by the nature and number of attached sugars, were included in the new molecules.
The base of the new technique is its starting point, a molecule that changes dynamics of the sugar-attachment reaction. Thorson explains,
“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.”
The new method is able to separate the sugar from its carrier and reattach it to the biological target molecule in a single test tube. He says,
“Sugars are involved in 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 variations of potential and existing medications is standard practice for drug-makers. A recently published investigation by Peltier-Pain and Thorson, showed that attaching a certain sugar to the anti-coagulant Warfarin kills its anti-clotting ability. However, the transformed molecule “suddenly becomes quite cytotoxic – it kills cells,” Thorson 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.”
Written by Grace Rattue