By Vincent Zurawski, PhD
Iron Chelator-Based Neurodegenerative Drug for Treatment of Wound Infections and MDR Bacteria
Occasionally, a chance alignment of circumstances can lead to an unexpected and highly productive outcome, one with the potential to induce a sea change in a particular field of endeavor. A novel small molecule called VK28, developed by Prof. Emeritus Moussa Youdim and his colleagues at the Technion and the late Prof. Abraham Warshawsky at the Weizmann Institute of Science, found its way to an unexpected collaborative research program involving Clinical Research Management contract researchers at the Walter Reed Army Institute of Research (WRAIR) in Silver Spring, Maryland, and at Varinel, Inc., the company to which VK28 had been licensed for commercial development.
VK28 - also known as VAR10100 - was originally developed by Youdim, Varinelís scientific founder, as a brain-selective and brain-permeable iron chelator, a chemical entity with the ability to bind up free iron. VK28 was designed to target treatment of neurodegenerative diseases such as Alzheimerís, Parkinsonís and Huntingtonís disease. An iron chelator penetrating the blood-brain barrier might be expected to bind up and remove free iron from brain cells, providing a neuroprotective effect by eliminating an important source of tissue-damaging free radicals that can be stimulated by the presence of iron. Free radicals are highly reactive and can severely damage and even kill the very cells we use to think. Indeed, Youdim and colleagues showed that, in two animal models of Parkinsonís disease, VK28 was not only neuroprotective, but also neurorestorative and lowered the toxic brain iron that accumulates.
ďThe emergence of MDR bacterial strains has become a significant challenge for clinicians and caregivers.Ē
During the product development process aimed at advancing VK28 to clinical trials, Varinel also developed a VK28 derivative called VAR10103 with potential as a drug candidate. As luck would have it, my son, Daniel Zurawski, is a principal investigator and contracted at WRAIR to develop new therapies and preventive medicines for wound infections, especially those involving multidrug-resistant (MDR) bacteria. The emergence of MDR bacterial strains has become a significant challenge for clinicians and caregivers of the U.S. military as wounded soldiers returning from Iraq and Afghanistan are often infected with bacteria that are resistant to most, if not all, current antibiotic treatment.
Because iron is an essential nutrient for all bacteria, including MDR bacteria, it was thought that treatment of wounds before or after a bacterial infection with an iron chelator alone or in conjunction with antibiotic therapy might provide the required antibacterial effect to keep infections in check. Sure enough, under the auspices of a Cooperative Research and Development Agreement (CRADA) between Varinel and the U.S. Army and Department of Defense, both VK28 and VAR10103 have proven effective, in the laboratory, at stopping bacteria in their tracks, and they have proven to be synergistic with certain antibiotics in targeting MDR-resistant organisms. These results were presented at the 2011 ICAAC Meeting in Chicago. At WRAIR, both compounds are now being tested in animal models of infection along with some other iron chelators that showed promise in vitro.
The same chemical entities with the potential to protect brain cells may also provide the means to deliver a knock-out punch to bacteria that would otherwise elude treatment. It all begins with the kind of solid scientific effort that is traditional at the Technion, and which has led to its world recognition.
Dr Vincent Zurawski is Founding President of Varinel and its Chief Scientific Officer.
Disclaimer: The findings and opinions expressed herein belong to the authors and do not necessarily reflect the official views of the WRAIR, the U.S. Army, or the Department of Defense.