SAN FRANCISCO, Calif.--Researchers at the San Francisco Veterans Affairs Medical Center and UC San Francisco have demonstrated that a type of drug known as a cysteine protease inhibitor may be highly effective against American trypanosomiasis or Chagas1 disease, which is caused by an infection with the parasite Trypansoma cruzi (T. cruzi).
Chagas is the leading cause of heart disease in Latin America and approximately 50,000 people die every year as a result of it. Once confined to Latin America, cases of Chagas1 disease have been reported in the United States. The study provides proof that this new class of protease inhibitors can be safely used in animals to treat a parasitic infection, the researchers said.
The study, published in the August 17 issue of the Journal of Experimental Medicine, reports on the treatment of 21 mice infected with lethal doses of T. cruzi. All of the treated mice were rescued from the infection. A control group of untreated mice all died within four to ten days. Some of the treated mice were followed for as long as a year with no evidence of disease or parasites.
Importantly, the cysteine protease inhibitors produced no side-effects in the animals, and there was no indication of drug resistance. According to senior author James H. McKerrow, MD, PhD, director of the National Institutes of Health-sponsored Tropical Disease Research Unit at the San Francisco VA Medical Center, and UCSF professor of pathology and pharmaceutical chemistry, the study demonstrates in mice that cysteine protease inhibitors stop T. cruzi from replicating by 3turning off2 a specific enzyme critical to the parasite1s survival -- much like aspartate protease inhibitors work against Human Immunodeficiency Virus (HIV).
Because cysteine and aspartate protease inhibitors function in similar ways, the researchers are optimistic about the drug1s safety and efficacy in humans.
While its potential as a Chagas treatment is very encouraging, perhaps equally important is that we have provided proof of the concept that cysteine protease inhibitors can stop a parasite from replicating without harming the host cell,2 says McKerrow. This proof of the concept could pave the way for new treatments for other kinds of infections, and perhaps for diseases such as cancer and arthritis which also involve the action of cysteine proteases, he says.
Chagas1 disease affects an estimated 16-18 million people throughout Latin America and approximately 90 million more are at risk. It is spread by the bite of certain blood-sucking insects and through transfusions with infected blood products.
At present the only therapies for Chagas1 disease are highly toxic and treatment must be carefully monitored by medical personnel. The current medications only cure about 60 percent of infections and, worse yet, in some geographical regions T. cruzi appears to be resistant to the commonly used medications.
T. cruzi primarily invades heart muscle and certain nerves, slowly destroying cells. When the parasite attacks the human heart, most victims become acutely ill for four to six weeks but then enter a chronic phase with few or no symptoms. However, during this quiet period, which can last for decades, T. cruzi continues to multiply and weaken the heart. As a result, the victim is slowly crippled and eventually dies as a result of heart failure.
Before cysteine protease inhibitors can be distributed for human use, they still must pass additional toxicology and safety studies which are currently underway. According to McKerrow, the preliminary results are promising. If approved by the Food and Drug Administration (FDA), McKerrow says the drug should be relatively inexpensive.
Co-investigators of the SFVAMC-UCSF study were Juan C. Engel, PhD, associate research parasitologist; Patricia S. Doyle, PhD, assistant research parasitologist; and Ivy Hsieh, MA, staff research associate; all of the UCSF Department of Pathology.
The study was funded with grants from the National Institutes of Health and the American Heart Association.
Three illustrations related to this news release are available on-line at http://www.ucsf.edu/pressrel/photos.html.
1. Computer image of the cysteine protease inhibitor molecule (blue object)
blocking the T. cruzi protease (pink ribbon).
2. Light microscopic images of cells infected with T. cruzi before and after treatment with cysteine protease inhibitor.
3. The Brazilian 10,000 Cruzado note (no longer in circulation) illustrated how prevalent the disease is in Latin America. The monetary note depicted the life cycle of T. cruzi along with its discoverer, Brazilian scientist Carlos Chagas, who first described the disease in 1909.