UC San Diego

Protozoan and helminth parasites of humans are common in areas of extreme poverty. Treatment of these infections relies on often antiquated drugs that are toxic and/or for which resistance has developed. New drugs are needed. Microtubule-(MT) modulators are established treatments for cancer and, more recently, as experimental treatments for neurodegenerative indications such as Alzheimer’s disease. Further, tubulin is a known molecular target in both parasitic protozoa and helminths. Herein, I first developed and optimized a robust automated assay to measure the motility of C. elegans, the nematode which is often used as a convenient parasite surrogate for the screening of anthelmintics. This assay was augmented by a visual assay to measure egg-hatching. Next, a collection of 38 MT-modulators was then screened at 50 µM in both assays and a number of ‘hits’ were discovered. Further optimization of the egg-hatching assay and additional screening of MT-modulators will be pursued. Lastly, in relation to Human African Trypanosomiasis (HAT), one MT-modulator was tested in a mouse model of Trypanosoma brucei infection for anti-parasite efficacy. After intraperitoneal administration at 5, 7.5 and 10 mg/kg to infected mice, the compound decreased parasitemia in the blood to below detectable levels and significantly extended the survival of mice relative to vehicle-treated infected controls. The data encourage the further pursuit of MT-modulators for the therapy of HAT.