A SPOONFUL OF SUGOIDS

A group of chemical compounds only recently identified by scientists is offering hope in the battle against HIV. Oliver Tickell investigates

POPULAR wisdom has it that cures for every human ailment are to be found among the multitudinous species of tropical rainforests. Perhaps. But Robert Nash, a botanist at the Institute of Grassland and Environmental Rersearch, Aberystwyth, is finding pharmaceutically interesting compounds closer to home. In potatoes, to be precise. And, more fragrantly, in bluebells and hyacinths.

Indeed a whole class of chemicals is emerging from these common plants that may soon be treating a host of diseases, cancer, Aids, diabetes, tuberculosis and hepatitis among them. These are chemicals that look just like sugars, but with one crucial difference - the oxygen that completes a sugar's carbon ring is replaced with nitrogen. Such molecules, so easily mistaken for sugars, are in fact alkaloids. They are generally known among scientists as "glycosidase inhibitors". I prefer another term: sugoids.

"It seems extraordinary that these compounds, which can reach several percent of dry weight, have escaped detection for so long," says Nash, "but it's easy to understand, really - unless you look very hard, you think you've got sugars." They are mainly present to protect the plants in which they occur, he believes, by making the plant material indigestible to insects and other herbivores.

Sugoids are biologically active in all kinds of other ways. First, let's go back to basics; or more particularly, to sugars and their fundamental role in the metabolism of every living organism from viruses to elephants to cabbages. Glucose alone, the most elementary of sugars, is active in at least 150 human metabolic pathways.

Sugars are used to transport energy around the body. Attached to complex proteins, they help them fold into their correct shape, stabilise them, or make them biologically active. They act as "area codes" to label molecules as they are transported around the body, ensuring they reach the right site. The sugar coating around mammalian eggs signals to sperm that they have reached their destination. Even blood group is determined by the way in which two simple sugars are linked on the surface of red blood cells.

Key to the diversity of roles played by sugars is the diversity of sugars themselves. Glucose, for example, has 64 sugar isomers, with an identical chemical composition but subtly different structures. "They might all look much the same to anyone who's not a chemist", says George Fleet, who specialises in synthesising sugars and other organic molecules at Oxford University. "But every biological system knows the difference between them."

Consider the confusion that can result from introducing sugoids into a living organism. Mistaken for sugars, they will be readily caught up in the organism's metabolism, but will suddenly turn around and do something completely unexpected - revealing themselves as chemical spanners in the metabolic works.

Current research is showing sugoids to have enormous therapeutic potential - as anti-virus agents, for example, though researchers emphasise that drugs will take a long time to develop. "Viruses are such fiendishly clever things," says Professor Raymond Dwek, head of Oxford's Glycobiology Institute. "They cover themselves in sugars to disguise themselves, making themselves look just like anything else, evading immuno-surveillance."

But the sugars that make viruses into such effective Trojan horses at a cellular level could also be their Achilles heel. Disrupt a virus's complex glycochemistry, and it will be weakened or even killed. By coincidence, the world's most feared virus is also its most heavily sugared. HIV's entire coat is plastered with sugars, which make up half of its weight - making it an obvious target for sugoid attack.

Indeed, several glucose mimics exhibit powerful anti-HIV activity. "Add them to a culture of HIV and the virus sticks aberrant sugars on its surface," says Dwek. "The virus can still bind to target cells, but it can no longer fuse with them so it is no longer infective." There is still much work to be done, however, before a workable drug is on the market. It's not much good, for example, if you need to eat ten kilos a day of a substance, however non-toxic, to produce a therapeutic effect.

At first the hepatitis-B Virus (HBV) didn't look likely to succumb to sugoids: the proteins underlying HIV's coat offer 25 binding sites for sugars, whereas HBV has just two. But work by Dwek, collaborating with Tim Block of Jefferson Medical College in Philadelphia, is yielding highly promising results. The sugoid known as NBDNJ - an analogue of glucose - has an amazing ability to mess the virus up. "Who would have guessed it?" asks Professor Dwek. "This is an absolutely incredible result."

HBV, it seems, relies on the presence of sugars attached to vital proteins to ensure they fold correctly into shape. Add NBDNJ, and the molecular assembly line that sticks the sugars on to the proteins is disrupted. When the wrongly-sugared protein comes to fold, it twists itself up into a hopeless jumble and the virus is unable to reproduce. This offers hope indeed for the world's 300m hepatitis-B sufferers.

Another disease which may be treatable with sugoids is non-insulin-dependent diabetes - a disease characterised by the liver's failure to regulate blood glucose concentrations. When blood glucose levels are low, the liver puts out glucose by breaking down its stores of glycogen. In diabetics, the liver continues to put out glucose even when blood glucose levels are high. The process is controlled by a glycosidase enzyme, glycogen phosphorylase, whose activity is reduced as glucose levels rise.

"If we had a glucose-like molecule that was more powerful, we would have a good regulating agent," says Professor Louise Johnson, head of Oxford's Laboratory of Molecular Biophysics. Her laboratory began by elucidating the three-dimensional structure of the enzyme, then designing sugoids to fit.

Next, George Fleet's team was put to work turning out made-to-measure sugoids. After examining over 50 molecules, one non-toxic glucose analogue turned out to be a thousand times stronger than glucose. "This is promising, but we need to improve the potency another tenfold to have a viable drug,'', says Louise Johnson.

Sugoids are also being put to work to try to prevent the spread, or metastasis, of cancers. Along with many other cells, cancer cells have a coating of the sugar mannose which allows them to escape immune detection. Introduce a mannose-like sugoid (or mannoid) to disrupt the coat-building, and the fast-reproducing cancer cells will be recognised and destroyed by the immune system.

Of course, other reproducing cells will also be messed up, but this doesn't matter in the short term. Swainsonine, a sugoid found in wild plants in Australia and the US, is almost the perfect mannoid for the job, says George Fleet. "The problem is that it's very toxic in other ways, so we are looking for other mannose mimics which are non-toxic but do exactly the same job."

In the future, sugoids are likely to find many other novel uses in many areas of human activity: a sugoid that disrupts the enzyme in sperm that bites through the egg's sugar coating might make a good contraceptive, for instance; hydantocidin, a sugoid made by fungi, is non-toxic to mammals but a potent killer of all perennial weeds; other sugoids are powerful insecticides and pest repellents. The age of the sugoid is surely nigh. !