Abstract
BackgroundSchistosomiasis, one of the world’s greatest neglected tropical diseases, is responsible for over 280,000 human deaths per annum. Praziquantel, developed in the 1970s, has high efficacy, excellent tolerability, few and transient side effects, simple administration procedures and competitive cost and it is currently the only recommended drug for treatment of human schistosomiasis. The use of a single drug to treat a population of over 200 million infected people appears particularly alarming when considering the threat of drug resistance. Quantitative, objective and validated methods for the screening of compound collections are needed for the discovery of novel anti-schistosomal drugs.Methodology/Principal FindingsThe present work describes the development and validation of a luminescence-based, medium-throughput assay for the detection of schistosomula viability through quantitation of ATP, a good indicator of metabolically active cells in culture. This validated method is demonstrated to be fast, highly reliable, sensitive and automation-friendly. The optimized assay was used for the screening of a small compound library on S. mansoni schistosomula, showing that the proposed method is suitable for a medium-throughput semi-automated screening. Interestingly, the pilot screening identified hits previously reported to have some anti-parasitic activity, further supporting the validity of this assay for anthelminthic drug discovery.ConclusionsThe developed and validated schistosomula viability luminescence-based assay was shown to be successful and suitable for the identification of novel compounds potentially exploitable in future schistosomiasis therapies.
Highlights
Parasitic flatworm trematodes or flukes of the genus Schistosoma cause schistosomiasis, one of the world’s greatest neglected tropical diseases
As chemotherapy relies on a single drug, praziquantel, many initiatives have been promoted aiming to search for novel anti-schistosomal drugs that can represent a valid alternative to the current treatment or could be used in case of emerging resistance
No vaccine is available against schistosomiasis, so that treatment and most of control initiatives rely on the long-term application of a single drug, praziquantel (PZQ)
Summary
Parasitic flatworm trematodes or flukes of the genus Schistosoma cause schistosomiasis, one of the world’s greatest neglected tropical diseases. The use of PZQ is limited by its stage-specific activity [4,5,6], since it is active on adult parasites (6–7 weeks and over) and it has minimal activity against juvenile worms (1–5 weeks old) The latter drawback can partially explain the low cure rates in high transmission areas where patients are likely to harbor juvenile and adult parasites concurrently [7]. The use of a single drug to treat a population of over 200 million infected people and over 700 million people at risk world-wide, appears worrisome when considering the threat of drug resistance. Praziquantel, developed in the 1970s, has high efficacy, excellent tolerability, few and transient side effects, simple administration procedures and competitive cost and it is currently the only recommended drug for treatment of human schistosomiasis. The use of a single drug to treat a population of over 200 million infected people appears alarming when considering the threat of drug resistance. Quantitative, objective and validated methods for the screening of compound collections are needed for the discovery of novel anti-schistosomal drugs
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