Screening a repurposing library, the Medicines for Malaria Venture Stasis Box, against Schistosoma mansoni.
BACKGROUND
The development of new treatments against schistosomiasis is imperative but lacks commercial interest. Drug repurposing represents a suitable strategy to identify potential treatments, which have already unblocked several essential steps along the drug development path, hence reducing costs and timelines. Promoting this approach, the Medicines for Malaria Venture (MMV) recently distributed a drug repurposing library of 400 advanced lead candidates (Stasis Box).


METHODS
All 400 compounds were initially tested in vitro against the larval stage of Schistosoma mansoni at 10 μM. Hits progressed to screening on adult worms and were further characterised for IC50, cytotoxicity and selectivity. Ten lead compounds were tested in mice harbouring a chronic S. mansoni infection.


RESULTS
Eleven of the 37 compounds active on the larval stage were also highly active on adult worms in vitro (IC50 = 2.0-7.5 μM). IC50 values on adult S. mansoni decreased substantially in the presence of albumin (7.5-123.5 μM). Toxicity to L6 and MRC cells was moderate. A moderate worm burden reduction of 51.6% was observed for MMV690534, while the other 9 compounds showed low activity. None of the in vivo results were statistically significant (P > 0.05).


CONCLUSIONS
Phenotypic screening of advanced lead compounds is a simple and resource-low method to identify novel anthelminthics. None of the promising hits of the Stasis Box identified in vitro against S. mansoni yielded acceptable worm burden reductions in vivo, which might be due to the high plasma protein binding. Since the in vitro hits interfere with different drug targets, they might provide a starting point for target based screening and structure-activity relationship studies.
['Pasche|Valérian|V|', 'Laleu|Benoît|B|', 'Keiser|Jennifer|J|']
D000818:Animals D000962:Antimalarials D055808:Drug Discovery D004353:Drug Evaluation, Preclinical D058492:Drug Repositioning D020128:Inhibitory Concentration 50 D007814:Larva D051379:Mice D012550:Schistosoma mansoni D012555:Schistosomiasis mansoni D012556:Schistosomicides D013329:Structure-Activity Relationship
Schistosoma mansoni Schistosomiasis Anthelminthics Drug discovery