Trial of T.cruzi DNA Vaccine in Experimental Model of Disease Challenge Infection
Chagas disease is caused by the parasite Trypansoma cruzi (T. cruzi) which is transmitted via the feces of an infected triatomine bug. In the early stages of infection, symptoms are flu-like with local swelling at the site of infection. After 4–8 weeks the immune system depletes much of the parasite from the body, and individuals usually enter an asymptomatic phase called the indeterminate phase of infection. Eventually 20-40% of infected individuals will develop life-threatening heart and digestive system disorders (called the determinate or chronic phase of infection). Nifurtimox and benznidazole are currently the only available therapies for Chagas disease. However, these drugs are not very effective in the chronic stage, and resistance is emerging. In addition, both drugs are mutagenic and have serious side effects, resulting in patients frequently abandoning the lengthy course of treatment (60-120 days).
Recent structural biology efforts have lent insight into requirements for cruzain inhibition, and our current efforts targeting cruzain are through development of backup leads to K777 and non-peptidyl inhibitors. Finally, new leads have been identified targeting CYP51, a key enzyme in the ergosterol synthetic pathway. Additional screening and chemical optimization of leads is in progress.
To expedite hit identification and lead characterization of novel anti-trypanosmal compounds, CDIPD scientists have developed a unique whole-parasite screen. Several new collaborations have been initiated around this assay including an NIH funded program with the Genome Novartis Foundation focused on development of a novel clinical candidate for treatment of Chagas.