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 Researchers identify new way to unmask melanoma cells to the immune system
17.01.2018 | Duke University Medical Center

nachricht Study advances gene therapy for glaucoma
17.01.2018 | University of Wisconsin-Madison

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: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

Im Focus: A thermometer for the oceans

Measurement of noble gases in Antarctic ice cores

The oceans are the largest global heat reservoir. As a result of man-made global warming, the temperature in the global climate system increases; around 90% of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Polymers Based on Boron?

18.01.2018 | Life Sciences

Bioengineered soft microfibers improve T-cell production

18.01.2018 | Life Sciences

World’s oldest known oxygen oasis discovered

18.01.2018 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>