Angewandte Chemie International Edition
© WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2004, 43 (29), 3818—3822
Reinforcing the Immune System
Small difference, large effect: fully synthetic drug is orders of magnitude more effective than naturally occurring analogue
Which is better, the original or a forgery? In this case the comparison works in favor of the "imitation": New York chemists set about copying a compound from sea sponges in the lab. The compound is known to stimulate the immune system, helping to fight several diseases. In their imitation, the researchers working with Richard W. Franck deliberately replaced a key atom. This small change in the molecular composition worked wonders—resulting in a substantially stronger immune stimulation.
The "original", KRN7000, is a highly promising pharmaceutical derived from a natural substance found in sea sponges. It originally gained attention for its astonishing antitumor activity in mice. As it turns out, the substance stimulates the immune system; it docks at a receptor on a certain type of immune cell and activates it. This allows the organism to defend itself much more effectively against certain types of cancer, as well as a number of other diseases, including malaria and hepatitis. The drug, which is well tolerated, is currently involved in clinical tests. KRN7000 is a glycolipid, meaning that it is made of a sugar and a lipid, a fat-like molecule. The sugar is bound to the lipid by one of the oxygen atoms of the sugar. Such a bond is called an O-glycoside. Can this drug be further improved by making some changes? For example, what happens if the oxygen atom is replaced by a carbon atom to make a C-glycoside? The chemists in the team were particularly interested in this question, because they had recently developed a method for the synthesis of C-glycosides. They thus worked out a synthetic strategy for the production of the C-glycoside variant of KRN7000.
Moriya Tsuji and the medics of the team compared the biochemical activities of the original and the imitation. The result? Mice were protected from malaria by both drugs, but the copy proved to be a thousand times more effective. The imitation was also a hundred times more effective than KRN7000 in protecting mice from the induction of lung tumors.
Why the synthetic C-glycoside is so much more effective has not yet been fully explained. Maybe because C-glycoside linkages are not as easily broken by enzymes in the body as the natural O-glycosides, they are able to remain active longer. Franck and his co-workers are leaning toward another explanation, however: The binding of the C-glycoside to the immune cell receptor seems to be of a somewhat different nature than that of the O-glycoside. This could trigger a different, more effective signal cascade within the immune cells.