The Discovery Of A Novel Series Of Compounds With Single-Dose Efficacy Against Juvenile And Adult Schistosoma Species

Author summary Schistosomiasis (also known as Bilharzia) is a severe disease with WHO estimates suggesting that more than 229 million people require preventative treatment. It is caused by parasitic worms which infect through the skin and, when mature, pair up in different parts of the body according to species, and produce eggs leading to significant adverse health impacts including death. Treatment is reliant on one drug, praziquantel, which is effective against adult worms, but has some disadvantages. Praziquantel is not effective against juvenile worms and is therefore unable to prevent the disease. Also, a large dose is required, and furthermore, reliance on one drug risks the development of drug resistance. This research describes the discovery of a new series of potent compounds, unrelated to praziquantel, which kill both the adult and juvenile parasitic worms in vitro, and in mice, following a low single oral dose. Predictions suggest that several of the compounds should be capable of curing infection in people with a single oral dose approximately 10-fold smaller than praziquantel.Treatment and control of schistosomiasis depends on a single drug, praziquantel, but this is not ideal for several reasons including lack of potency against the juvenile stage of the parasite, dose size, and risk of resistance. We have optimised the properties of a series of compounds we discovered through high throughput screening and have designed candidates for clinical development. The best compounds demonstrate clearance of both juvenile and adult S. mansoni worms in a mouse model of infection from a single oral dose of < 10 mg/kg. Several compounds in the series are predicted to treat schistosomiasis in humans across a range of species with a single oral dose of less than 5 mg/kg.