New Class Of Protease Inhibitors May Be Effective In Treating One Of Latin America's Most Devastating Diseases

August 18, 1998

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.

Images Available

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.
-end-


University of California - San Francisco

Related Infection Articles from Brightsurf:

Halving the risk of infection following surgery
New analysis by the University of Leeds and the University of Bern of more than 14,000 operations has found that using alcoholic chlorhexidine gluconate (CHG) halves the risk of infection in certain types of surgery when compared to the more commonly used povidone-iodine (PVI).

How plants shut the door on infection
A new study by an international team including University of Maryland scientists has discovered the key calcium channel responsible for closing plant pores as an immune response to pathogen exposure.

Sensing infection, suppressing regeneration
UIC researchers describe an enzyme that blocks the ability of blood vessel cells to self-heal.

Boost to lung immunity following infection
The strength of the immune system in response to respiratory infections is constantly changing, depending on the history of previous, unrelated infections, according to new research from the Crick.

Is infection after surgery associated with increased long-term risk of infection, death?
Whether experiencing an infection within the first 30 days after surgery is associated with an increased risk of another infection and death within one year was the focus of this observational study that included about 660,000 veterans who underwent major surgery.

Revealed: How E. coli knows how to cause the worst possible infection
The discovery could one day let doctors prevent the infection by allowing E. coli to pass harmlessly through the body.

UK study shows most patients with suspected urinary tract infection and treated with antibiotics actually lack evidence of this infection
New research presented at this week's European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Amsterdam, Netherlands (April 13-16, 2019) shows that only one third of patients that enter the emergency department with suspected urinary tract infection (UTI) actually have evidence of this infection, yet almost all are treated with antibiotics, unnecessarily driving the emergence of antimicrobial resistance.

Bacteria in urine doesn't always indicate infection
Doctors should think carefully before testing patients for a urinary tract infection (UTI) to avoid over-diagnosis and unnecessary antibiotic treatment, according to updated asymptomatic bacteriuria (ASB) guidelines released by the Infectious Diseases Society of America (IDSA) and published in Clinical Infectious Diseases.

Subsidies for infection control to healthcare institutions help reduce infection levels
Researchers compared three types of infection control subsidies and found that under a limited budget, a dollar-for-dollar matching subsidy, in which policymakers match hospital spending for infection control measures, was the most effective at reducing the number of hospital-acquired infections.

Dengue virus infection may cause severe outcomes following Zika virus infection during pregnancy
This study is the first to report a possible mechanism for the enhancement of Zika virus progression during pregnancy in an animal model.

Read More: Infection News and Infection Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.