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

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.

Mechanically produced schistosomula as a higher-throughput tools for phenotypic pre-screening in drug sensitivity assays: current research and future trends

“…These drugs are usually dissolved in dimethylsulphoxide (DMSO) to obtain drug stock solutions of 10 mg/ml or 10 mM and then diluted into culture media to serve as positive control [12, 20, 23, 25, 26, 34]. The highest concentration of DMSO used as drug solvent should not exceed 1% [15, 18, 24, 34].…”

“…Antifungal drug (Amphotericin B) and antibiotic drugs (penicillin 100 to 300 U/ml and streptomycin 100 to 300 μg/ml) are used to supplement the medium in order to avoid fungal and bacteria contamination during schistosomula culture [12, 17, 23, 25–27, 34]. …”

“…For the optimal culture condition for schistosomula, several studies have shown that the supplemented medium is appropriate. Different concentrations of heat inactivated fetal calf serum (iFCS) 1% [24], 5% [12, 20, 23, 25–27, 34, 38], 10% [17, 37], or heat inactivated fetal bovine serum (FBS) 5% [38], 10% [36] have been used.…”

“…The supplemented medium 199 turned out to be the most suitable medium for the incubation of schistosomula and thus has been widely used for in vitro screening of others compounds with known activities against Schistosoma newly transformed schistosomula [12, 23–25, 34]. Thus 5 to 10% heat inactivated calf serum is the commonly used supplement by several researchers.…”

Schistosomiasis therapeutics: whats in the pipeline?

“…Merck KGaA has a library of molecules available for screening for schistosome drug targets, and the recent identification of 121 compounds active against the schistosomula and 36 compounds active against the adult schistosome stage, from a library screen of 1,600 FDA-approved compounds supported by the Gates-funded drug discovery project, overseen by the Drugs for Neglected Diseases initiative offers some hope for discovering potential drug candidates. [29] In the current climate, where there are no schistosome drugs on the horizon, we are proposing a paradigm shift for the future of anti-schistosome therapeutics, optimizing the benefits of PZQ in four ways:…”