Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Basic research producing new anthrax therapies

23.08.2004


Thanks to new screening tools, and some luck, researchers at the University of Chicago have discovered three unrelated compounds that inhibit the two toxins – edema factor and lethal factor -- that have made anthrax one of the most feared of potential bioterror agents.

In the August 2004 issue of the journal Chemistry and Biology, the researchers report that they used a novel screening technique, developed at the University, to find a small molecule that prevents edema factor from connecting to its target within the cell.

A similar approach, reported in Nature Biotechnology in May, resulted in a compound that inhibits lethal factor, the other anthrax toxin. And a study published in PNAS in February showed that a drug already approved to treat hepatitis was also effective in the lab against edema factor.



"This is dramatic example of how progress in basic science can be applied quickly, effectively and unpredictably to clinical problems," said Wei-Jen Tang, Ph.D., associate professor in the Ben May Institute for Cancer Research at the University of Chicago and an author of all three studies. "Our lab began working with edema factor as a tool to understand basic cellular metabolism, but the knowledge we gained soon led us to three potential therapies."

Because each drug disrupts a different link of the chain of toxic events, the therapies should be complementary. Although all three treatments appear promising in the test tube, none has yet been tested clinically caution the authors. Cell culture and animal testing is underway.

Until 2001, Bacillus anthracis, the bacterium that causes anthrax, was an obscure agricultural pathogen, but that fall someone sent letters stuffed with anthrax spores to several politicians and journalists. Nearly half (5/11) of those infected by breathing in the spores died from the disease. The anthrax mailings triggered a run on antibiotics, but these drugs only work in the early stages of anthrax infection, before the bacteria have had time to spread and secrete toxins. "These attacks called attention to the need for better therapies for anthrax infection," said Tang.

Fortunately, the Tang lab was already studying edema factor, using it as a molecular probe to understand cell-cell communication. His team had sent a manuscript describing the three-dimensional structure of anthrax edema factor to the journal Nature a few days before the first terrorist use of the microbe became public.

In that paper, Tang and colleagues showed how edema factor did its damage. Inside an infected cell, edema factor connects with a protein called calmodulin. Calmodulin changes the toxin’s shape, creating a conformation that functions just like a cellular enzyme called adenylyl cyclase, which helps regulate cell-to-cell signaling.

When edema factor connects with calmodulin, however, it becomes a relentless version of adenylyl cyclase – 1,000-fold more potent -- causing affected cells to become hyperactive. These cells devour their energy stores, lose the ability to regulate their environment, release water, causing edema (swelling) in surrounding tissues, and die.

Because of the bioterrorist attacks a few months before, the discovery received widespread attention. A researcher at a pharmaceutical company happened to notice newspaper accounts of the work and suspected that a drug he studied, called adefovir dipivoxil, acted on the same metabolic pathway. He sent Tang several candidate compounds and Tang’s lab found that the active metabolite of adefovir also blocks edema factor.

The Chemistry and Biology paper describes a more systematic and less fortuitous approach. Tang and colleague Milan Mrksich, Ph.D., professor in the department of chemistry and the Institute for Biophysical Dynamics at the University of Chicago, used the combination of two screening methods, developed by Tang and Mrksich, to examine a library of 10,000 compounds in search of small molecules that inhibited edema factor.

They uncovered one that very effectively prevented edema factor from binding to calmodulin. Although this compound was itself quite toxic, the researchers were able to make slight modifications that removed the toxicity without altering its ability to block edema factor. They named their non-toxic version Nitro10506-2A.

This discovery followed a report from Tang and Mrksich in May that used a similar approach to identify a compound that halts the activity of lethal factor, the other anthrax toxin, in laboratory tests. Lethal factor shreds a protein that helps cells stay healthy. The compound they found, called DS-998, blocks lethal factor’s harmful cutting action.

Nitro10506-2A and DS-998 could lead to the development of new drugs for the treatment of anthrax, Tang said, but he cautioned that research remains in the early stages. "Discovering proteins that have roles in disease processes is the first step in the drug discovery process," added Mrksich, "but still a very long way from the actual development of a drug."

The National Institutes of Health and the National Science Foundation funded the study. Additional authors include Young-Sam Lee, Pamela Bergson and Wei Song He of the University of Chicago.

John Easton | EurekAlert!
Further information:
http://www.uchicago.edu
http://www.uchospitals.edu

More articles from Life Sciences:

nachricht Hunting pathogens at full force
22.03.2017 | Helmholtz-Zentrum für Infektionsforschung

nachricht A 155 carat diamond with 92 mm diameter
22.03.2017 | Universität Augsburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Pulverizing electronic waste is green, clean -- and cold

22.03.2017 | Materials Sciences

Astronomers hazard a ride in a 'drifting carousel' to understand pulsating stars

22.03.2017 | Physics and Astronomy

New gel-like coating beefs up the performance of lithium-sulfur batteries

22.03.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>