A new era for chagas disease drug discovery?
Recent clinical trials investigating treatment of chronic indeterminate Chagas disease with two re-purposed azole anti-fungal drugs, posaconazole and ravuconazole, revealed their inferiority to the current standard-of-care benznidazole and highlighted the inadequacy of the existing pre-clinical testing paradigm for this disease. A very limited number of controlled clinical trials for Chagas disease have been conducted to date. The selection of these compounds for clinical evaluation relied heavily on pre-clinical data obtained from in vitro screens and animal studies. This chapter reviews the evolution of CYP51 as a target for Trypanosoma cruzi growth inhibition and also explores the impact of clinical trial data on contemporary Chagas disease drug discovery. Advances in pre-clinical profiling assays, the current compound landscape and progress towards the identification of new drug targets to re-invigorate research are reviewed.
Epichem Pty Ltd, Perth, Western Australia, Australia.
Martine
M
Keenan
Epichem Pty Ltd, Perth, Western Australia, Australia.
Jason H
JH
Chaplin
D058888:14-alpha Demethylase Inhibitors / Q000627:therapeutic use; D014355:Chagas Disease / Q000188:drug therapy*; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D006801:Humans; D009593:Nitroimidazoles / Q000627:therapeutic use
D058888:14-alpha Demethylase Inhibitors; D009593:Nitroimidazoles; C009999:benzonidazole
Benznidazole; CYP51; Chagas disease; Clinical trial; Drug re-purposing; Neglected tropical disease; Phenotypic screening; Screening cascade; Sterol 14α-demethylase; Trypanosoma cruzi