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HIVís new enemy? Small molecule with broad antibacterial value shows mettle against HIV
March 2006
by Jeffrey Bouley  |  Email the author


DENVER óCeragenix has reported that a synthetic small molecule in a class of compounds called ceragenins (CSAs)óa class it licensed exclusively from Brigham Young University (BYU) in large part for its antibacterial propertiesóis showing evidence that it could be useful in fighting human immunodeficiency virus (HIV).
In fact, in vitro laboratory tests conducted at Vanderbilt University in Nashville , Tenn. indicate that this particular CSA may have potent virucidal activity against multiple strains of HIV.
"We found that CSA-54 potently inhibits HIV infection of primary human CD4+ T cells, the virus's in vivo targets, and was not toxic to epithelial cells at concentrations significantly higher than those required to kill the virus," says Dr. Derya Unutmaz, associate professor of microbiology and immunology at Vanderbilt. "In addition, CSA-54 killed a wide range of HIV isolates and completely blocked genetically engineered HIV that enters the cells independent of the cell surface receptor the virus normally uses."
This finding, Unutmaz notes, indicates that CSA-54 likely attacks the viral membrane and disrupts the virus from interacting with its target cells, similar to some of the known microbicidal peptides.
"This is particularly important as a compound that targets the viral membrane is likely to be effective against all strains of the virus, regardless of mutations as the viral membrane remains unchanged," he says.
"We are encouraged, based on these early in vitro studies, that CSAs may provide a completely unique family of anti-infectives, potentially active against a wide range of viral, fungal and bacterial targets, including those resistant to current therapies," says Steven Porter, CEO of Ceragenix. "Given the potent activity of CSA-54 against all strains of HIV tested, we plan on exploring the use of this compound in both topical and systemic applications for HIV therapy."
CSAs were invented by Dr. Paul D. Savage of BYU's Department of Chemistry and Biochemistry and exclusively licensed to Ceragenix. CSAs have a net positive charge that is electrostatically attracted to the negatively charged cell membranes of certain viruses, fungi and bacteria. CSAs have a high binding affinity for such membranes and are able to rapidly disrupt the target membranes leading to rapid cell death.

One of the most interesting features of CSAs is a mechanism-of-action that is similar to that of antimicrobial peptides, which form part of the body's innate immune system, notes Carl Genberg , senior vice president of research and development for Ceragenix. Thus, he says, they avoid many of the difficulties associated with the use of antimicrobial peptides as medicines.

"A lot of our work follows in the footsteps of research on antimicrobial peptides and so that is a research area we are always interested in looking at to see whether our products might work as well as peptides would," Genberg says.

CSAs also provide a potential cost advantage over peptides, he notes. "Our compounds are simpler and easier to make and lower cost than long-chain peptides," he explains. A single milligram of Magainin, for example, can cost more than $100. "But we can easily produce CSAs in gram quantities, and will give 50 mL away free to interested researchers."

Ceragenix's work on pharmaceutical compounds from CSAs is still precommercial, Genberg notes, as much of the last two years of work with Savage at BYU has been focused on discovering the range of activity of the compounds. Work is now shifting more toward toxicity, dosage and route-of-administration issues.

Code: E030603



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