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Activity profile of an FDA-approved compound library against schistosoma mansoni.

Abstract

AUTHOR SUMMARY: For a disease of large global health importance, schistosomiasis has a disproportionally small treatment tool box- only praziquantel is used to treat all 3 major forms of the disease. While drug discovery can be a long, laborious and expensive process, especially for an under-funded neglected disease such as schistosomiasis, drug recycling (also termed repositioning or repurposing) can bypass some of the development processes and offset the costs. We conducted a drug screening project of 1600 FDA-approved compounds from a very diverse set of indications against Schistosoma mansoni. The full 1600 compounds were first screened in vitro against the larval stage of the worm, of which 121 drugs were identified as active. These hits were then screened on the adult stages of the worm in vitro where 36 of these hits were also found to be active on the adult stage. The safety and pharmacokinetic profiles of hit compounds were then compared to their in vitro activity and 11 compounds were chosen for studies in mice. Of these, clofazimine and doramectin were found to be moderately active, and present new antischistosomal scaffolds with which further investigations can be pursued. Our findings are placed in context with results obtained from previous in vitro and in silico chemogenomics work and agreements and disagreements discussed.

BACKGROUND: As 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.

METHODOLOGY: 1600 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 FINDINGS: The 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/SIGNIFICANCE: The 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.

 

More information

Type
Journal Article
Author
Panic G
Vargas M
Scandale I
Keiser J