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Scientists Develop ’Super Peptide’ That Kills Candida Albicans

21.02.2003


Fungus Responsible For Nearly All Yeast Infections


Discovery May Unravel 300 Million Year Old Molecular Mystery

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»CZEN

Zengen, Inc. announced today that its scientists have developed a ’super’ peptide that kills Candida albicans (C. albicans), a single-celled organism that is the most prevalent yeast species in the human gastrointestinal (GI) tract. A common fungus, C. albicans causes a variety of infections, including vaginitis. This organism can invade tissues and produce fatal infections in individuals with compromised immune systems such as those suffering from HIV/AIDS or undergoing organ or bone transplants.

This discovery, say the researchers, may also be a key to understanding one of the greatest mysteries of Mother Nature - how a peptide that has existed in the same form since at least the Pennsylvanian period of the Paleozoic era (more than 300 million years ago) really works in modulating inflammatory and immune responses.


The study, "Novel a-Melanocyte Stimulating Hormone Peptide Analogues with High Candidacidal Activity," is scheduled to appear in the February 20, 2003 issue of the Journal of Medicinal Chemistry, a peer-reviewed journal of the American Chemical Society, the world’s largest scientific society.

Scientists aimed to find a-MSH analogues with greater antimicrobial activity and to reach a better understanding of the peptide structure-antifungal activity relations against C. albicans through design, synthesis and testing of novel peptide analogues in which several modifications were made. Because previous data suggested that antimicrobial effects of a-MSH were receptor-mediated, the research team chose to focus on the a-MSH amino acid sequence (6-13), which contains the invariant core sequence His-Phe-Arg-Trp (6-9) that is important for binding to the known melanocortin receptors. A second focus was on the sequence Lys-Pro-Val (11-13) that is known to be important for antimicrobial activity.

In this structure-activity study, the team developed several compounds that have greater candidacidal activity than a-MSH and, in fact, one particular peptide (number 19) killed nearly 100 percent (99.7 percent) of Candida cells over repeated experiments. Further, results indicate that substitutions in the a-MSH (6-13) amino acid sequence can either enhance or reduce candidacidal influences of the peptide. This discovery may help scientists understand the unique mechanism of action of a-MSH peptides, which are substantially different from that of most antimicrobial agents that cause direct damage to the microbial membrane.

"The power of this new a-MSH analogue against C. albicans appears to be significantly greater than any other known peptides, as it is super-potent, super-stable and super-durable," stated Paolo Grieco, Associate Professor, Department of Pharmaceutical Chemistry and Toxicology, University of Naples, Italy, and lead author on the paper. "We’ve not only improved upon Mother Nature by developing a ’super’ peptide that kills C. albicans, but also may have unlocked the key to understanding how a-MSH really works - through a receptor in yeast which is yet to be identified."

Unlike viruses or bacteria, fungal cells such as yeast resemble the cells of the human body and thus, can be difficult to treat. There is increasing evidence that C. albicans strains become resistant to current treatments -- enabling these fungi to take on ’super’ powers.

"This new peptide analogue appears to be different from the known anti-microbial peptides, such as a-MSH, that have been around for hundreds of millions of years," said Ettore Novellino, Professor and Dean of the Faculty of Pharmacy, University of Naples, Italy, and co-author of the paper. "Clearly there is more research to be conducted on Zengen’s novel molecules and we are excited about the enormous clinical implications of our discovery."

Zengen’s proprietary molecules were developed from more than 25 years of original research in the US, Europe and Asia on peptide molecules derived from alpha-Melanocyte-Stimulating Hormone (a-MSH). A naturally occurring molecule, a-MSH modulates inflammatory and immune responses. James Lipton, Ph.D., Zengen’s chief scientific officer, chairman of the scientific advisory board and director, and his collaborators first demonstrated that a-MSH possesses anti-inflammatory properties and uncovered the specific activity of the carboxy-terminal tripeptide region (C-terminal peptide) of the a-MSH peptide. These discoveries led to the development of Zengen’s proprietary peptide molecules, including CZEN 002, a synthetic octapeptide. Zengen is currently conducting phase I/II clinical trials with CZEN 002 in vaginitis.

"Ultimately these new findings, coupled with results from ongoing research with our proprietary molecules, such as our clinical trials in vaginitis with CZEN 002, could lead to the development of valuable pharmaceutical agents to control yeast growth," added Dr. Lipton, study co-author. "This holds tremendous promise to change the way inflammatory and infectious diseases are treated."

About Candida albicans

While the Candida species (including C. albicans, as well as non-albicans C. parapsilosis, C. tropicalis, C. kefyr, C. krusei and C. glabrata) are all part of the normal flora of the mucocutaneous membranes, C. albicans accounts for approximately 80 to 95 percent of all yeast infections. A simple, single-celled organism crucial for brewing beer and baking bread, C. albicans is a common inhabitant of healthy humans that causes numerous fungal infections including thrush, diaper rash, esophagitis and infections in women. It is common in hospital settings and this simple fungus can be deadly - leading to life-threatening infections in people with compromised immune systems, such as those diagnosed with HIV/AIDS or undergoing organ or bone marrow transplants. Moreover, if it gets into an individual’s bloodstream, C. albicans can grow in kidneys or heart valves, particularly artificial valves, thereby causing heart failure or even death.

There is increasing evidence that C. albicans strains become resistant to common available treatments. Further, available drugs have certain side effects such as burning, itching and irritation and some, such as oral azoles, suffer the drawback of potential systemic toxicity. An additional shortcoming of treatment with current agents is their limited efficacy in certain diseases, such as vaginitis, caused by non-C. albicans species.

About Zengen, Inc.

Zengen, Inc. is a biopharmaceutical company focused on discovering, developing and commercializing innovative products to treat and prevent infection and inflammation through application of its proprietary peptide technologies. Zengen’s novel molecules offer broad-based anti-infective and anti-inflammatory solutions for multiple diseases and disorders, ranging from yeast infection to transplantation, and have the potential to significantly alter the way these diseases are treated. For more information about Zengen, please visit www.zengen.com.

Kumiko Hakushi | Ruder Finn, Inc
Weitere Informationen:
http://www.zengen.com

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