Abstract
Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs. In most cases, control is reliant upon praziquantel (PZQ) monotherapy. However, PZQ is ineffective against sexually immature parasites, and there have also been several concerning reports on cestode and trematode infections with poor PZQ cure-rates, emphasizing the need for alternative therapies to treat these infections. We have revisited a series of benzodiazepines given the anti-schistosomal activity of meclonazepam (MCLZ). MCLZ was discovered in the 1970's but was not brought to market due to dose-limiting sedative side effects. However, in the decades since there have been advances in our understanding of the benzodiazepine GABAA receptor sub-types that drive sedation and the development of sub-type selective, non-sedating ligands. Additionally, the sequencing of flatworm genomes reveals that parasitic trematodes and cestodes have lost GABAAR-like ligand gated anion channels, indicating that MCLZ's anti-parasitic target is distinct from the human receptors that drive sedation. Therefore, we have screened a library of classical and non-sedating 1,4-benzodiazepines against Schistosoma mansoni and identified a series of imidazobenzodiazepines that immobilize worms in vitro. One of these hits, Xhe-II-048 also disrupted the parasite tegument, resulting in extensive vacuole formation beneath the apical membrane. The hit compound series identified has a dramatically lower (~1000×) affinity for the human central benzodiazepine binding site and is a promising starting point for the development of novel anti-schistosomal benzodiazepines with minimal host side-effects.
Highlights
Over 200 million people are infected with the parasitic blood flukes that cause the neglected tropical disease schistosomiasis [1], and over 90% of infections occur in sub-Saharan Africa where the disease kills approximately 280,000 persons/year [2, 3]
The benzodiazepine meclonazepam (MCLZ) is an effective anti-schistosomal drug, but the sedative side effects of MCLZ coincide with the anti-parasitic dose [15]
The sedative side effects of MCLZ are likely driven by human GABAARs– those heteromeric receptors that contain the α1 subunit [19]
Summary
Over 200 million people are infected with the parasitic blood flukes that cause the neglected tropical disease schistosomiasis [1], and over 90% of infections occur in sub-Saharan Africa where the disease kills approximately 280,000 persons/year [2, 3]. PZQ treatment has high cure rates of 70–90% [6, 7], but it is concerning that a subset of infections in human and animal populations appear to be refractory to treatment [8,9,10], either due to PZQ’s lack of efficacy against recently acquired, immature parasites [11, 12] or standing genetic variation in parasite populations The latter possibility is especially concerning in regard to the potential emergence of PZQ-resistant parasites, and consideration needs to be given to whether PZQ-monotherapy will be sufficient to achieve schistosomiasis elimination [13]. We have profiled the repertoire of S. mansoni ligand gated ion channels and, having found no obvious parasite GABAARs, screened a library of benzodiazepines to identify compounds that display anti-parasitic activity and exhibit reduced mammalian GABAAR affinity
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