Designing new drugs for the treatment of Chagas disease
Chagas disease is a significant health and economic burden, with more than 5 million people affected globally. The disease is endemic in South and Central America although it is becoming more prevalent in other regions including the USA, Europe and Australia as a result of travel and migration. Currently available drug treatments for this disease are inadequate due to long treatment regimens and frequent side effects.
Chagas disease is caused by an insect-transmitted parasite, Trypanosoma cruzi. Despite much effort, the discovery of new drugs to treat Chagas disease has been hampered by many factors including inadequate in vivo models of acute and chronic T. cruzi infections, as well as a poor appreciation of the underlying pharmacokinetic/pharmacodynamic (PKPD) properties a potential drug might need in order to treat a chronic infection.
How did the facility help?
The Centre for Drug Candidate Optimisation (CDCO) is part of a consortium of drug discovery scientists brought together by the Drugs for Neglected Diseases initiative (DNDi) to discover new drugs to target Chagas disease. The project team also includes parasite biologists at Griffith University (Queensland) and the London School of Hygiene and Tropical Medicine (UK) and medicinal chemists at Epichem Pty Ltd (Perth). The CDCO contributes expertise in defining the biopharmaceutical properties and PKPD relationships for potential candidate compounds thereby providing critical information to inform medicinal chemistry so that structures can be refined and improved.
An in vivo model of Chagas disease using bioluminescence imaging technology to monitor parasite burden in real time has been validated using known and potential anti-Chagas drugs (Scientific Reports, 2016; 6:35351). Parallel PK investigations by the CDCO provided the link between biological efficacy and drug concentrations for the validation set. The project team has also evaluated >2500 molecules using a high-throughput in vitro screen for assessing T. cruzi activity. Based on their T. cruzi activity and a rigorous assessment of their potential drug-like properties by the CDCO, three of the most promising series have been selected for late stage optimisation following positive results in the in vivo efficacy model. The project team are aiming to select a clinical drug candidate by the end of 2017.
This work is supported in part by an ARC linkage grant with DNDi as the partner organisation. The CDCO integrates leading edge biopharmaceutical expertise with chemistry and biology to enhance the development potential of new drug candidates. Through its collaborations, the CDCO has contributed to programs that have progressed 24 novel drug candidates into clinical development in disease indications including cancer, CNS disorders, cardiovascular disease and infectious diseases. The Drugs for Neglected Diseases initiative (DNDi) is a collaborative, not for profit organisation whose mission is to develop new drugs and treatments for the world’s most neglected diseases (www.dndi.org).