Abstract
BackgroundThe 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).MethodsAll 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.ResultsEleven 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).ConclusionsPhenotypic 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.
Highlights
The development of new treatments against schistosomiasis is imperative but lacks commercial interest
For IC50 determination on adult worms, cytotoxicity assays and in vivo studies, MMV690732 and MMV690787 were purchased from Adooq Bioscience (Irvine, USA), MMV690596, MMV690599 and MMV690646 were purchased from Bio-Techne (Minneapolis, USA), MMV690466 and MMV690765 were purchased from SanBio BV/Cayman (Uden, The Netherlands), MMV690684 was purchased from Selleck Chemicals (Houston, USA), MMV690534 and MMV001539 were purchased from Sigma-Aldrich (Buchs, Switzerland)
The highest activities were observed for MMV003452 and MMV690684 revealing IC50 values of 7.5 and 7.7 μM, respectively, denoting a 2-fold increase compared to the values observed without albumin supplementation
Summary
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, 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). As the return on investment for a new antischistosomal treatment is expected to be very low (or inexistent), drug repurposing is a cost-effective solution to expand the pool of therapeutic candidates This approach enables the bypassing of certain steps of the development process, which reduces the cost of research and development (R&D) and shortens the “bench to market” period without compromising safety [15, 16].
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