Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

LSUHSC research shows drug blocks enzyme that activates bacterial and viral toxins

18.11.2002


A paper published in the December, 2002 issue of Infection and Immunity by a research team at the Louisiana State University (LSU) Health Sciences Center in New Orleans provides clear evidence that the lethal toxins of such infectious bacteria as Pseudomonas and anthrax can be blocked by a drug developed at the LSU Health Sciences Center in New Orleans. The compound, called D6R (hexa-D-arginine), is a potent, stable, small molecule inhibitor of furin.



Bacteria produce a number of toxins which rapidly enter and kill cells. In anthrax, the lethal factor toxin must bind to another part of the anthrax toxin, called the PA molecule, before it can enter and destroy a cell. But before binding can occur, the PA molecule produced by the bacteria must be made smaller. Furin, a protein-cutting enzyme or protease, which sits on the outside of cells, cuts the PA molecule, making it small enough for the lethal factor toxin to attach. Lethal factor toxin cannot bind to PA that has not already been cut by furin; therefore, without cut PA, lethal factor toxin loses the ability to bind to and enter the cell, and becomes harmless.

Working on the theory that if the action of furin could be blocked, the toxins would not be activated and therefore unable to kill cells, the research team set out to make a peptide that would suppress furin activity. In collaboration with a research group in California (Torrey Pines Institute for Molecular Studies), the LSUHSC group developed the furin inhibitor, D6R, for which a patent application has now been filed. The LSUHSC research group under the direction of Dr. Iris Lindberg, Professor of Biochemistry, included current postdoctoral fellow Dr. Miroslav S. Sarac, and past fellow Dr. Angus Cameron.


In the current paper, the LSUHSC research scientists examined the therapeutic potential of D6R against Pseudomonas aeruginosa exotoxin, both in cell culture and in live animals (mice). Various concentrations of D6R were tested, with no apparent side effects, regardless of dose. (However, no tissue microhistology has yet been done, and these studies are needed to reveal any subtle damaging effects.) The survival rate of cells in culture 48 hours after treatment with D6R–given at the same time as Pseudomonas toxin-- was significant–50%. The survival rate of the group of mice treated with D6R for two days prior to administration of toxin was also about 50% at seven days. The group of mice treated with D6R at the same time toxin was administered showed a 25% survival rate.

Pseudomonas aeruginosa is an opportunistic pathogen causing urinary tract infections, respiratory system infections, dermatitis, soft tissue infections, bacteremia and a variety of systemic infections, especially in those with immunosuppression related to cancer, HIV and severe burns. P. aeruginosa is known for its resistance to antibiotics. Although some antibiotics are effective against some strains, even those antibiotics are not effective against all strains.

Sepsis, a systemic infection, is the leading cause of death among critically ill patients in the US. It is estimated that about 750,000 American people develop sepsis each year and that more than 200,000 die from it. One of the factors contributing to the high mortality of sepsis (which has increased more than 90% in the last 20 years according to the National Vital Statistics Report, 2000,) is damage from excessive production of cytokines (chemical messengers of the immune system). The LSUHSC scientists found that D6R was not only able to protect cells from lethal toxins, but to do so without invoking a cytokine response itself. D6R also dramatically lowered the production of one cytokine, TNF.

According to the researchers, D6R appears to exhibit a number of potentially promising attributes. It is able to cross cell membranes; it is small enough to achieve useful therapeutic concentrations; and it exhibits no apparent toxicity at concentrations 100x therapeutic levels. It could also prove useful in treating infection from other viruses and bacteria whose toxins are dependent upon furin activity for activation. Besides Pseudomonas and anthrax, these include Ebola, clostridium, diphtheria, shiga, RSV, HIV-1, infectious bronchitis and yellow fever among others.

Dr. Lindberg was recently awarded a grant by the National Institute of Allergy and Infectious Diseases to test D6R against anthrax toxin in both cells as well as animal models (rats and mice). She will further examine the structural requirements of D6R-related molecules against furin with the idea of eventually using D6R (or a better drug developed through these studies) as a therapeutic drug for anthrax, Pseudomonas and other furin-dependent infections. She will also conduct safety and toxicity studies during the grant period.

"This is very exciting research," said Dr. Lindberg. "We hope that D6R-like furin inhibitors will represent effective and potent new drugs that will not only prove a viable approach to combat some types of bacterial infection, but also add to our country’s bioweapons defense arsenal."

Leslie Capo | EurekAlert!
Further information:
http://www.lsumc.edu/

More articles from Health and Medicine:

nachricht Microgel powder fights infection and helps wounds heal
14.11.2018 | Michigan Technological University

nachricht Spread of deadly eye cancer halted in cells and animals
13.11.2018 | Johns Hopkins Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: A Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

Im Focus: Coping with errors in the quantum age

Physicists at ETH Zurich demonstrate how errors that occur during the manipulation of quantum system can be monitored and corrected on the fly

The field of quantum computation has seen tremendous progress in recent years. Bit by bit, quantum devices start to challenge conventional computers, at least...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

Massive impact crater from a kilometer-wide iron meteorite discovered in Greenland

15.11.2018 | Earth Sciences

When electric fields make spins swirl

15.11.2018 | Physics and Astronomy

Discovery of a cool super-Earth

15.11.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>