Novel approach to discovering drugs for Chagas disease

Mexican researchers highlight a novel approach to discovering drugs for Chagas disease in a laboratory study reported in PLoS Neglected Tropical Diseases.

Chagas disease, caused by the parasite Trypanosoma cruzi, affects about 18 million people in the American continent. Unfortunately, there is no satisfactory treatment for the disease: the existing drugs have severe side effects, require long courses of treatment, and show variable effectiveness.

In the new study, Armando Gómez-Puyou (Universidad Nacional Autonoma de Mexico, Mexico City) and colleagues report results of their search for molecules that could eliminate the parasite. Their work targets an enzyme in the parasite called triosephosphate isomerase.

One of the problems with identifying molecules that attack parasitic enzymes is that most of these enzymes have a counterpart in the human host—and so the molecule may also attack the human enzyme (causing side effects in humans). But triosephosphate isomerase, which has two subunits, holds promise as a possible target because the human form differs from the parasitic form. Armando Gómez-Puyou and colleagues found significance differences in the interface between the two subunits in triosephosphate isomerase from Homo sapiens and that from Trypanosoma cruzi. They therefore searched for molecules that could specifically disrupt this interface in the parasitic form of the enzyme but not the human form.

In their search, they discovered that dithiodianiline (DTDA) is far more effective at inactivating the parasitic form of the enzyme than the human form, and its detrimental effect is due to it perturbing the interface between the two subunits.

By targeting this interface, the researchers say, “it is possible to discover small molecules that selectively thwart the life of the parasite.”