Probing a parasite for vulnerability

From Miami, Fla., at a meeting of the American Society of Tropical Medicine and Hygiene

In their quest to find a weakness in the single-celled parasite that causes African sleeping sickness, researchers have identified an enzyme that appears indispensable to the microbe’s survival. Disabling this enzyme could offer a novel treatment strategy for the disease, says biochemist Theresa C. O’Brien of the University of California, San Francisco.

Sleeping sickness is caused by the bite of a tsetse fly carrying the protozoan Trypanosoma brucei. Earlier work showed that a compound called Z-Phe-Ala-CHN2 could kill the microbe in a lab dish. This compound is known to inhibit protein-chopping enzymes called proteases. Although scientists suspected that protease inhibition killed T. brucei, the compound’s specific target was unknown.

When O’Brien and her colleagues sought out proteases in T. brucei, they discovered one that was previously unknown. The scientists named this version of a human protease called cathepsin-B TbcatB (for T. brucei cathepsin B).

To test whether Z-Phe-Ala-CHN2 was killing the parasite by inhibiting TbcatB, the researchers interfered with the cellular mechanisms that underlie TbcatB’s manufacture. That also killed the parasite, O’Brien says.

Further tests revealed that the protozoan needs TbcatB to obtain iron, which it typically draws from its human host. So, the lethal effect of the protease inhibitor may be to disrupt this iron supply line, O’Brien hypothesizes.

Z-Phe-Ala-CHN2 is not itself a strong drug candidate because it inhibits many proteases, some of which are beneficial. A better drug against T. brucei would specifically target an enzyme, such as TbcatB, that is essential to the parasite but inconsequential to people.

It turns out that people make seven cathepsins, whereas the parasite makes only two. That suggests that the parasite may be much more vulnerable to a drug aimed at a single cathepsin than people are, says James McKerrow, also of the University of California, San Francisco.

The researchers are screening a library of compounds in search of chemical agents that inhibit only TbcatB. Such a compound might form the basis of a sorely needed new drug for this deadly disease.

Existing treatments for African sleeping sickness that were developed over the past 80 years can cause severe side effects. They’re effective if given early in the disease’s progression, but their performance is inconsistent in later stages of the disease, McKerrow says.