By Mary Welch

For some scientists in biotechnology, devising ways to combat biological weapons is as much of a challenge as finding cures for cancer and AIDS.

Government money for biological-warfare research is becoming increasingly available, and companies such as San Diego-based Isis Pharmaceuticals Inc., whose Ibis Therapeutics program recently received a $6.6 million grant, say they are working on Schwarzenegger-like compounds to defeat a biological enemy.

¿You need a whole new approach, because of the nature of the problem,¿ said David Ecker, vice president and managing director of Ibis. ¿You have to swing for the fence.¿

More biotechnology firms are exploring the opportunities in the biological-defense effort.

Cynthia Edwards, chief scientific officer for Genelabs Technologies Inc., of Redwood City, Calif., said the research often has a ¿large practical application¿ beyond biological defense. Genelabs has a $13.6 million grant to create a database that will help the rapid design of drugs to counter pathogens employed in biological warfare.

¿There is new impetus to create antibacterial, antifungal and other drugs,¿ Edwards said. ¿The biotechnology companies are attempting to develop a new field of drugs, which will get the interest of the pharmaceutical companies, once lead compounds are identified.¿

The Ibis grant, from the Defense Advanced Research Projects Agency (DARPA), a part of the U.S. Department of Defense, is similar to a number of such grants given to companies with ¿extraordinary¿ ideas, Ecker said. ¿We¿re all looking at dealing with the situation of what would happen if a terrorist, or simply a deranged person, decided to use bacteria or virus for deadly purposes,¿ he said.

¿The whole area is vast,¿ he added. ¿You have companies working on combating bacterial and viral problems; you have other toxins. Then, you have companies working on how to detect the threat, and decontaminating the site.¿

This most recent endowment to Ibis builds on a 1997 grant focused on developing a strategy to identify common binding sites to a wide range of bacteria, in order to develop small molecules to combat bacterial pathogens. This work has yielded a number of propriety targets and significant advances in the design of RNA-targeted drugs.

¿There are a dozen bacteria and viruses that might be used in terrorist biological warfare, and that¿s not counting bacteria that as been manipulated in a malicious way that we haven¿t anticipated,¿ Ecker said. ¿For instance, it could become more virulent, [and] God knows what else,¿ Ecker said.

What Ibis is seeking is a far-reaching solution that ¿jumps outside the box of classical biology,¿ he said. ¿The problem with classical biology is that there might be a gap from the time an incident occurs to getting a solution.¿

Ibis is researching drug targets for bacteria that have the potential to be universal ¿ that is, which are RNA-based. RNA is unique in that it is critical to the life cycle of pathogens and is an excellent binding site for small molecules.

Seeking Drugs That Bind Rapidly

That¿s where Ibis¿ partner, HNC Software Inc., comes in. HNC, with its Predictive Software Solutions, has developed a pattern recognition system called Context Vector Technology (CVT).

¿It¿s like, sometimes you can figure out or infer a word based on the content of the words around it,¿ Ecker said.

The companies hope that conserved RNA structures can be discovered purely from gene sequence information rapidly and automatically using CVT, which offers the potential for dramatically speeding up the currently labor-intensive and time-consuming comparative sequence analysis process used for initial RNA structure discovery.

By using infrared multi-photon dissociation with mass spectrometry, a speed-up can be achieved over current techniques for characterizing the full three-dimensional structure of RNA. The end result is the identification of lead compounds of small molecules that specifically bind to the identified targets.

¿When we find these targets, we have to come up with a strategy and find a drug that binds to the target very rapidly, because the biological warfare agents may work very rapidly,¿ Ecker said.

Ibis isn¿t the only beneficiary of the government¿s largesse. A year ago, Genelabs received a three-year, $13.6 million grant ¿ more than one-third of the $30 million planned for the three-year Unconventional Pathogen Countermeasures Program launched by DARPA. (See BioWorld Today, Feb. 12, 1998, p. 1.)

Initially the project focused on building a database with targets to be identified later. Genelabs has two projects funded by DARPA, both for the discovery of nucleic acid-binding drugs. The DNA-binding technology is targeted to the discovery of broad spectrum antimicrobial drugs. The RNA-binding drug program is specifically developed to create drugs with broad spectrum anti-RNA viral activity.

¿During the first year, we have been able to demonstrate the activity of a DNA-binding molecule in regulating the expression of human gene in cell culture, without toxicity to the cell,¿ Edwards said. ¿In addition, we have shown the ability to regulate the expression of a gene in bacterial cells in a dose-dependent manner.¿

In the RNA-binding drug program, Genelabs also has identified compounds with strong preference for RNA over other nucleic acid structures, and antiviral screening of these compounds is under way.

¿We are very pleased with the rapid progress made to date in both of these programs; because our discovery programs target mechanisms that are universal and fundamental to virtually all organisms and disease processes, the progress we make in the DARPA program is immediately applicable to commercially attractive therapeutic areas,¿ Edwards said.

Vaccine Program Also Under Way

Last October, Nanogen Inc., of San Diego, received a pledge of more than $8 million over the next five years, from two government agencies to create an advanced miniaturized lab for biological warfare defense applications.

Another program is the Joint Vaccine Acquisition Program, a $322 million, 10-year project to test, store and protect U.S. armed forces against potential biological warfare agents. The program was developed to ensure that the military would have access to a supply of FDA-approved vaccines effective against potential biological warfare agents.

OraVax Inc., of Cambridge, Mass., is participating with DynPort LLC., of Reston, Va., on development and manufacture of such vaccines.

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