Discovery of novel antischistosomal scaffolds from the open access Pandemic Response Box

ABSTRACT

Background

Treatment and control of schistosomiasis rely on a single drug, praziquantel. New orally active antischistosomals featuring novel molecular scaffolds are urgently needed to prevent the emergence of resistance.

Methods

We screened 400 drug-like compounds contained in the open-access Pandemic Response Box (PRB) against newly transformed schistosomula (NTS) at a concentration of 10 µM scoring death, changes in motility, and morphological alterations. Compounds displaying an activity ≥66% at 72 h underwent testing against adult Schistosoma mansoni in vitro. Fast-acting (≥66% at 24 h), nontoxic drugs focusing on late-stage and approved drugs were investigated in the patent S. mansoni mouse model.

Results

We identified 26 hits active against NTS, of which 17 elicited ≥66% activity against adult S. mansoni following 24 h of drug exposure. The highest activity against adult S. mansoni was observed with MMV1581558 (EC₅₀ value of 0.18 ± 0.01 µM) and nitazoxanide (0.47 ± 0.07 µM). Of the five compounds tested in vivo, MMV1581558 and the approved drug ozanimod reduced average worm burden versus controls by 42 % and 36 %, respectively, after a single oral dose of 200 mg/kg bodyweight in mice harboring a chronic S. mansoni infection.

Conclusion

MMV1581558 discovered from screening the PRB represents a novel antischistosomal scaffold with high in vitro antischistosomal activity amenable to chemical modification for drug development.

KEYWORDS:

• Anthelminthics
• drug discovery
• drug repurposing
• Pandemic Response Box
• Schistosoma mansoni
• schistosomiasis

Acknowledgments

We would like to gratefully thank the Medicine for Malaria Ventures (MMV, www.mmv.org) for their support and supplying the compounds.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Authors’ contributions

SB and JK conceived and designed the experiments. SB and CH performed the experiments. SB analyzed the data and drafted the first version of the manuscript. JK revised the manuscript. All authors read and approved the final manuscript.

Supplementary material

Supplemental data for this article can be accessed here.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The authors are grateful to the Swiss National Science Foundation for financial support [No. 320030_175585].