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Biotech / Medical : Ionis Pharmaceuticals (IONS) -- Ignore unavailable to you. Want to Upgrade?

To: Greg Rich who wrote (2514)	3/8/1999 9:32:00 AM
From: emil	Read Replies (2) \| Respond to of 4676

From the Yahoo thread: www.darpa.mil/dso/rd/upc/0003.html Drugs to Protect Against Engineered Biological Warfare Bacteria -------------------------------------------------------------------------------- Isis Pharmaceuticals Carlsbad, CA David Ecker (Principal Investigator), decker@isisph.com -------------------------------------------------------------------------------- There are many species of infectious bacteria that might be used in biological warfare or terrorism, including organisms deliberately made more virulent or resistant to all existing antibiotics. Should our citizens or troops be suddenly infected with an unknown genetically modified organism, there would be insufficient time to identify the organism, determine its weakness (if any) and treat the exposed victims. Effective countermeasures require that we discover and deploy a new type of drug that works by a mechanism that kills allbacteria, no matter how they have been modified, without harming humans or animals. To achieve this objective, we have developed a strategy to find structures in RNA common to all species of bacteria, but absent in humans and animals. If such “bacterial signature structures” truly exist, a drug discovery effort focused on these structures could result in new compounds that kill bacteria with unprecedented breadth in their spectrum of activity. We are developing new technology to achieve this goal by: 1.) Analyzing the RNA from hundreds of bacterial species to find biologically essential structures common to all bacteria; 2.) Predicting and experimentally verifying the three dimensional shape of these structures; 3.) Using computational methods to design “virtual” molecules likely to fit into the shape; 4.) Synthesizing thousands of molecules based upon the virtual molecule templates; 5.) Developing new techniques to detect the tight and specific binding of our molecules to the RNA targets; 6.) Determining which of the molecules effectively kill bacteria without harming human cells; 7.) Evaluating the most effective antibacterial molecules in animal models of infection with a wide variety of bacterial species. Over the past year we have made progress in each of these objectives. With a collaborating group of evolutionary and structural biologists, we analyzed RNA structures from hundreds of bacterial species and identified an initial set of common structures as potential drug targets. We are continuing to improve and automate our strategy to identify common RNA structures and will continue to add targets to our discovery effort. We have also made progress on techniques to predict the 3-dimensional structure of RNA and are in the process of confirming our first structure prediction by NMR spectroscopy. Our present combinatorial chemistry methods and automated synthesis instrumentation have the potential to make up to 10,000 molecules in a single day. We also developed software that records the exact molecular structure of each molecule and generates its synthesis instructions for the automated synthesizer. Thus far, we have designed molecules likely to bind our selected drug targets and synthesized an initial set of over 100,000 molecules. We developed high throughput screening techniques to find inhibitors of our RNA targets and identified some initial leads that kill bacteria. To match the high throughput capabilities of our chemical synthesis program, we are developing a unique screening technology for RNA targets based upon mass spectrometry. In initial mass spectrometry experiments that take only minutes to complete, we were able to measure over 500 molecules binding to an RNA target. With further development and automation of this technology we anticipate the ability to screen up to 2,000,000 molecules against 10-20 RNA targets per year. When our program is fully implemented, we will have designed, synthesized and tested an extraordinarily large collection of molecules exclusively focused on RNA targets. We expect this integrated drug discovery strategy to produce drug leads that have the spectrum of activity necessary for effective biological warfare countermeasures. Last Updated: Mar 18, 1998