Research Article: Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni

Date Published: July 31, 2015

Publisher: Public Library of Science

Author(s): Gordana Panic, Mireille Vargas, Ivan Scandale, Jennifer Keiser, Charles Cunningham.

Abstract: BackgroundAs plans to expand mass drug treatment campaigns to fight schistosomiasis form, worries about reliance on praziquantel as the sole available treatment motivate the investigation for novel antischistosomal compounds. Drug repurposing might be an inexpensive and effective source of novel antischistosomal leads.Methodology1600 FDA approved compounds were first assayed against Schistosoma mansoni schistosomula at a concentration of 10 µM. Active compounds identified from this screen were advanced to the adult worm screen at 33.33 µM, followed by hit characterization. Leads with complementary pharmacokinetic and toxicity profiles were then selected for in vivo studies.Principal FindingsThe in vitro screen identified 121 and 36 compounds active against the schistosomula and adult stage, respectively. Further, in vitro characterization and comparison with already available pharmacokinetic and toxicity data identified 11 in vivo candidates. Doramectin (10 mg/kg) and clofazimine (400 mg/kg) were found to be active in vivo with worm burden reductions of 60.1% and 82.7%, respectively.Conclusions/SignificanceThe work presented here expands the knowledge of antischistosomal properties of already approved compounds and underscores variations observed between target-based and phenotypic approaches and among laboratories. The two in vivo-active drugs identified in this study, doramectin and clofazimine are widely available and present as novel drug classes as starting points for further investigation.

Partial Text: Worldwide, schistosomiasis continues to affect the health and quality of life of millions, causing 3.3 million Disability-Adjusted Life-Years lost [1]. Most of the burden is contained in the tropics, mostly in Sub-Saharan Africa, where it disproportionally affects children in poor rural areas [2]. The three principal causative agents are Schistosoma mansoni, Schistosoma haematobium and Schistosoma japonicum. Infection with any of these three species, when left untreated, results in chronic inflammation which slowly develops into swelling, fibrosis and necrosis of the tissues of intestinal organs, the liver or the bladder, as well as a range of other symptoms which gradually impair the host physiologically and even cognitively [3,4].

The advent of praziquantel in the 1970s was a great milestone for the control of schistosomiasis in that finally, a safe, cheap and effective drug became available that could be used to treat millions in cost-effective preventive chemotherapy campaigns. Unfortunately, the success of praziquantel also resulted in many labs and firms choosing to drop further investigations on their leads [19]. This, along with inadequate attention and funding has rendered the antischistosomal arsenal dangerously dependent on a single drug [10].



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