Aiming a World of Computers at Anthrax

A multiple-sponsor distributed computing project launched Jan. 22 aims to derail anthrax's ability to enter human cells and eliminate the toxin as a terrorists' weapon. 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 began last April and still continues.1 Headed by professor Graham Richards, chairman of chemistry at Oxford and director of the NFCR Centre for Computational Drug Design there, the cancer project—as of Jan. 23—had enlisted the aid of almost 1.3 million computers around the world and generated almost 81.1 years of computing time screening small molecules against possible anti-cancer drug targets. United Devices posts regular statistical updates on its Web site (www.ud.com). In that project, computer users around the world download a screensaver program that receives instructions when online, screens molecules in silico for binding sites on specific cancer-related proteins, then sends results back to a primary server—all while working in the background. Richards' team will research the "hits" that appear and investigate potential drugs. Turning the researchers' attention toward anthrax seemed to be a natural next step. "We were prompted to go into it because after Sept. 11, such was the excitement and dismay about the anthrax problem that Nature published—prepublished, in fact—the structures of the proteins involved in the anthrax toxin,"2 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.3 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."4 When the researchers used that software on the anthrax proteins, results came quickly.5 "It's one of these cases where, when you see what it's found, you think, 'Oh my god, that's obvious,'" Richards said. In the NFCR Centre at Oxford, Richards has a database of 3.5 billion small molecules that can be screened against the anthrax protein, which is lethal only under specific conditions. Three components make up the toxin: protective antigen, lethal factor, and edema factor. The Pannifer research2 showed that only the complete toxin is lethal; the Mourez research3 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 with seven copies of the protein for the lethal factor to enter a cell, but the specific binding site was unknown until the Richards group expanded on the earlier research. Their results indicate 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 screensaver program (Windows only) can be downloaded from www.intel.com/cure, www.ud.com, or www.researchforacure.com. If a computer already is running the previous screensaver for cancer research, the program is set up to either replace the cancer element or alternate between cancer and anthrax. The results to be derived from the anthrax project, which Richards describes as "lists of molecules that look like strong candidates to become drugs," will be passed on freely to the US and UK governments. In addition to being a philanthropical gesture, there is a practical reason for that, Richards says: "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." Larry Hand can be contacted at lhand@the-scientist.com. References 1. L. Hand, "Computing for cancer research," The Scientist, 15[10]:1, May 14, 2001. 2. A.D. Pannifer et al., "Crystal structure of the anthrax lethal factor," Nature, 414:229-33, Nov. 8, 2001. 3. M. Mourez et al., "Designing a polyvalent inhibitor of anthrax toxin," Nature Biotechnology, 19:958-61, October 2001. 4. M. Glick et al., "Identification of ligand binding sites on proteins using a multi-scale approach," Journal of the American Chemical Society, in press. 5. M. Glick et al., "Protection against anthrax: Identification of a site for rational drug design," Nature Biotechnology, in press.

Aiming a World of Computers at Anthrax

Interested in reading more?

Become a Member of