Cells, like pills, are sugar-coated. This covering makes them sweet, in a manner of speaking, to microbes, which often fasten themselves to a cell's outer layer. In the past few years researchers have come to realize that this feature plays a crucial role in other important processes as well--including inflammation and organ rejection. Now a small but growing number of pharmaceutical companies are designing medicines to target surficial, sugar-binding proteins.
Sugars--which are often linked in small clusters to form oligosaccharides--have so far lagged proteins in medical research because they were hard to analyze. Two sugar molecules, for instance, can be connected in 22 different ways. Automated equipment, however, is making analysis easier, and new methods of synthesis suggest a boom for the field. Even Ole Hindsgaul of the University of Alberta, a leading carbohydrate chemist who criticizes exaggerated claims for biotechnology, says the area has "extraordinary promise."
One sugary reaction underlying inflammation has already proved a commercial goal. White cells in the blood are captured when damaged tissues produce proteins called selectins, which stick to the characteristic four-sugar oligosaccharides on the leukocytes' surface. Interfere with this sticking, the theory goes, and a damaging overaccumulation of such cells--and the resulting inflammation--might be avoided.
Cytel in San Diego is furthest along in developing a drug that would do exactly that. The company has produced a modified sugar molecule that mimics the oligosaccharide selectins bind to, creating a decoy; selectins should connect harmlessly to the drug instead of to white blood cells. Cytel's compound is being tested in patients to see if it can prevent the inflammatory heart damage, known as reperfusion injury, that often occurs after blood flow has been restored in a heart-attack victim.
Glycomed in Alameda, Calif., which was bought earlier this year by Ligand Pharmaceutical, also has what Hindsgaul terms "an excellent class" of selectin inhibitors. Researchers there are also working on carbohydrates that interfere with growth of blood vessels, as well as some that disrupt the enzymes tumor cells need in order to spread.
Mindful of the importance of cell-surface sugars to bacteria, a few manufacturers are examining carbohydrates for potential anti-infective powers. Neose Pharmaceuticals in Horsham, Pa., is testing an oligosaccharide that may suppress infections of helicobacteria in the stomach, which can lead to ulcers. The bacteria will, according to Neose, bind to its drug rather than to the sugars. The company says it is also experimenting with a sugar that may give infant formula some of the infection-fighting properties of breast milk; a more ambitious effort aims to block the sugar-based immune reaction that makes it impossible to transplant organs from baboons and other primates into people.
Some compounds may even work to enhance the capabilities of microbe-fighting cells. Alpha-Beta in Worcester, Mass., for instance, has a multisugar molecule that appears to prevent postoperative infections.
Whereas most researchers in this growing field rely on natural or engineered enzymes to make their sugary molecules, at least one company is pursuing a different tack. Daniel Kahne of Transcell in Princeton, N.J., says he has developed a rapid technique to synthesize oligosaccharides chemically. This process could produce compounds unlike any seen in nature. Because many antibiotics and antitumor agents contain sugars as part of their structure, new variants might improve the effectiveness of such medications.
By attaching carbohydrates to biological molecules in novel ways, Transcell has made so-called permeation enhancers, which ferry drugs across cell membranes, making even large molecules suitable for administration by mouth. "We have sound animal data showing that proteins and peptides can be made orally bioavailable in dogs," states Elizabeth E. Tallett, chief executive of Transcell. Clinical trials with one permeation-enhanced antibiotic may start within a year. High-tech approaches such as gene therapy and antisense compounds might also benefit.
Despite all the advances, a potential drawback to sugar-based medicines might be that many of them are too easily digested to be given as pills. So Oxford GlycoSystems in England is searching for more robust molecules that mimic oligosaccharides. The company already has one promising candidate, a chemical that might attract anticancer drugs to the liver by binding to the organ's cells. Several other large pharmaceutical manufacturers are also working on mimetic compounds. It appears that biotechnology, which has long labored with protein-based drugs, might yet discover that sugars can provide the all-important icing.--Tim Beardsley
SCIENTIFIC AMERICAN August 1995 Volume 273 Number 2 Page 34
Scientific American (ISSN 0036-8733), published monthly by Scientific American, Inc., 415 Madison Avenue, New York, N.Y. 10017-1111. Copyright 1995 by Scientific American, Inc. All rights reserved. Except for one-time personal use, no part of any issue may be reproduced by any mechanical, photographic or electronic process, or in the form of a phonographic recording, nor may it be stored in a retrieval system, transmitted or otherwise copied for public or private use without written permission of the publisher. For information regarding back issues, reprints or permissions, E-mail SCAinquiry@aol.com.
