PHILADELPHIA — A project launched this week will use PC power to search for molecules that might block the anthrax toxin from entering human cells. The ambitious project has the backing of computer giants Intel and Microsoft, distributed computing specialist United Devices, the chemistry department at the University of Oxford, UK, and the National Foundation for Cancer Research (NFCR).

The anthrax project comes on the heels of a successful similar effort in cancer research that the same team began last April. Headed by Graham Richards, chairman of chemistry at Oxford and director of the NFCR Centre for Computational Drug Design there, the cancer project uses the power of idle PCs to screen small molecules for sites that might bind to cancer-related proteins. The screensaver program then sends results back to a primary server. It has so far enlisted the aid of almost 1.3 million computers around the world and generated almost 81.1 years of computing time.

Turning the team's attention toward anthrax seemed to be a natural next step. "We were prompted to go into it because after September 11, such was the excitement and dismay about the anthrax problem that Naturepublished — prepublished, in fact — the structures of the proteins involved in the anthrax toxin," Richards told The Scientist. "And, of course, as in our cancer project, we'd get nowhere without a crystal structure to start with. In this case, however, there's one extra intellectual step. Although the structures of the proteins were known, a binding site that would be suitable for rational drug design was not known. But there was a clue. Some work from Harvard had shown that a short length of peptide bound to an artificial polymer does block anthrax in rats. And we could see that this string of peptides then must be binding somewhere."

Richards continued, "By sheer good fortune, within my research group, work done by postdoc Meir Glick and my collaborator Guy Grant has produced some software that enables one to take a protein and a small molecule and find out where it will bind." When the researchers used that software on the anthrax proteins, results came quickly. "It's one of these cases where, when you see what it's found, you think, 'Oh my god, that's obvious,'" Richards said.

Three components make up the toxin: protective antigen, lethal factor and edema factor. Pannifer et al. had shown that only the complete toxin is lethal; Mourez et al. identified a peptide that, when bound to a flexible polymeric backbone, prevented the toxin from assembling in vitro and blocked it from being toxic in rats. The protective antigen must form a ring composed of seven copies of the protein for the lethal factor to enter a cell, but it was not known where the peptide binds to block toxin assembly until the Richards group expanded on the earlier research. Their results indicated that the peptide may bind to the protective antigen heptamer at an area that interacts with the edema and lethal factors.

"I suspect that the seven proteins in the ring must help form a pore through the cell wall," explained Richards. "When we found the binding site, it is just exactly where these things would bind together, so if you could put a drug into that position, you would stop the proteins combining and then we hope — and, of course, it is still a hope — we would stop anthrax from getting into the cell."

He continued, "So, having done that, we're in the position exactly as we were with cancer — that is, we have a protein with a very well-defined binding site, and we can now on that basis try out our database of 3.5 billion molecules."

And even though this project is about anthrax, it's not entirely unrelated to cancer research: "Because tumor cells assemble deadly molecules the same way harmful bacteria create toxins, cancer research can shed valuable light [on] other diseases and create new medicines," said Sujuan Ba, NFCR science director.

The results to be derived from the anthrax project, which Richards described as "lists of molecules that look like strong candidates to become drugs," will be passed on freely to the US and UK governments. There is a practical reason for that, Richards said: "Going from a drug candidate to an actual drug would require an enormous input of funds, and it's not the sort of thing that a pharmaceutical company would be very likely to do, because if you made a pill against anthrax, you wouldn't sell any because no one's got the problem. It's the sort of thing that a government might want to invest in to protect its people."

This article will appear in The Scientist, 16[3]:17, 2002