Identification of annotated bioactive molecules that impair motility of the blood fluke Schistosoma mansoni

Duguet, Thomas; Glebov, Anastasia; Hussain, Asimah; Kulkarni, Shashank; Mochalkin, Igor; Geary, Timothy G.; Rashid, Mohammed H.; Spangenberg, Thomas; Ribeiro, Paula

doi:10.1016/j.ijpddr.2020.05.002

Cited by 15 publications

(11 citation statements)

References 80 publications

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“…While some biological discrepancies were observed between our study and that conducted by Debbert et al. [ 49 ], likely due to differentially-employed experimental processes [ 50 ], broadly overlapping anti - S. mansoni activities were found with these six compounds. However, we herein have added a substantial body of additional work that more broadly explored the anti-schistosomal activities of both dianilinoquinoxalines and 6-nitroquinoxalines (or 6-acyl derivatives); these supporting data include activities against S. mansoni juveniles (compound 22 only) and sporocysts (compounds 22, 22a, 22c, 22d, 22f, 25, 26, 28, 30, 31, 32, 33, 34, 35, 36 and 37) as well as adult S. japonicum (compounds 22, 25, 26, 30, 31, 33 and 35) and S. haematobium worms (compounds 22, 30, 31 and 33).…”

Section: Resultscontrasting

confidence: 92%

Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation

Padalino

El-Sakkary

Liu

et al. 2021

European Journal of Medicinal Chemistry

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Schistosomiasis is a neglected disease of poverty that is caused by infection with blood fluke species contained within the genus Schistosoma . For the last 40 years, control of schistosomiasis in endemic regions has predominantly been facilitated by administration of a single drug, praziquantel. Due to limitations in this mono-chemotherapeutic approach for sustaining schistosomiasis control into the future, alternative anti-schistosomal compounds are increasingly being sought by the drug discovery community. Herein, we describe a multi-pronged, integrated strategy that led to the identification and further exploration of the quinoxaline core as a promising anti-schistosomal scaffold. Firstly, phenotypic screening of commercially available small molecules resulted in the identification of a moderately active hit compound against Schistosoma mansoni (1, EC 50 = 4.59 μM on schistosomula). Secondary exploration of the chemical space around compound 1 led to the identification of a quinoxaline-core containing, non-genotoxic lead (compound 22). Compound 22 demonstrated substantially improved activities on both intra-mammalian (EC 50 = 0.44 μM, 0.20 μM and 84.7 nM, on schistosomula, juvenile and adult worms, respectively) and intra-molluscan (sporocyst) S. mansoni lifecycle stages. Further medicinal chemistry optimisation of compound 22, resulting in the generation of 20 additional analogues, improved our understanding of the structure-activity relationship and resulted in considerable improvements in both anti-schistosome potency and selectivity (e.g. compound 30; EC 50 = 2.59 nM on adult worms; selectivity index compared to the HepG2 cell line = 348). Some derivatives of compound 22 (e.g. 31 and 33) also demonstrated significant activity against the two other medically important species, Schistosoma haematobium and Schistosoma japonicum . Further optimisation of this class of anti-schistosomal is ongoing and could lead to the development of an urgently needed alternative to praziquantel for assisting in schistosomiasis elimination strategies.

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Section: Resultscontrasting

confidence: 92%

Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation

Padalino

El-Sakkary

Liu

et al. 2021

European Journal of Medicinal Chemistry

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“…The subtracted pixels represent a change in parasite position over time and are used as a metric to measure worm´motility (66). These methods were employed to evaluate the effect of different compounds on schistosome NTS/adults worms, such as tyrosinederived signaling agonists/antagonists (74), natural alkaloids (75)(76)(77) and analogs (77,78), as well as others with biological activity in humans (e.g., NPS-2143, a calcium-sensing receptor antagonist) (77).…”

Section: Image-based Methodsmentioning

confidence: 99%

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence

et al. 2021

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Schistosomiasis is a parasitic disease caused by trematode worms of the genus Schistosoma and affects over 200 million people worldwide. The control and treatment of this neglected tropical disease is based on a single drug, praziquantel, which raises concerns about the development of drug resistance. This, and the lack of efficacy of praziquantel against juvenile worms, highlights the urgency for new antischistosomal therapies. In this review we focus on innovative approaches to the identification of antischistosomal drug candidates, including the use of automated assays, fragment-based screening, computer-aided and artificial intelligence-based computational methods. We highlight the current developments that may contribute to optimizing research outputs and lead to more effective drugs for this highly prevalent disease, in a more cost-effective drug discovery endeavor.

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“…The advantage of our assay is that more advanced stages, i.e., juveniles (liver stages) can be cultured under in vitro conditions and utilized in primary screening. Therefore, in the quest for alternatives to PZQ, drug repurposing have been extensively explored as it would allow accelerating the development timelines [36][37][38][39][40]. With our optimized in vitro assay for the generation of S. mansoni juveniles, we have screened a total of 340 approved drugs from NCATS library [15].…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium

et al. 2021

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Background Anthelminthic treatment options against schistosomiasis are limited. The current treatment relies almost exclusively on a single drug, praziquantel (PZQ). As a consequence, the development of resistance to PZQ and limited activity of PZQ against earlier development stages are respectively a risk and a limitation to achieving the goals of the new WHO roadmap towards elimination. For the discovery of new chemical starting points, the in vitro drug screening on Schistosoma mansoni (S. mansoni) against newly transformed schistosomula (NTS) is still the most predominant approach. The use of only NTS in the initial screening limits sensitivity to potential new compounds which are predominantly active in later developmental stages. Using our recently described highly standardized, straightforward and reliable culture method that generates high rates of juvenile worms, we aimed to repurpose a subset of the NCATS Pharmaceutical Collection (340 compounds) to identify new hits with an in vitro worm culture assay. Methodology/Principal findings Cercariae were mechanically transformed into skin-stage (SkS) schistosomula and continuously cultured for 3–6 weeks to the liver stage (LiS). A commercial source of serum was identified, and decrease of NTS/well along with optimal drug testing conditions was established to test compounds on early and late LiS worms. The library was screened in 96-well format assays using praziquantel (PZQ) as a positive control. Primary screening allowed a 5.9% hit rate and generated two confirmed hits on adult worms; a prophylactic antianginal agent and an antihistaminic drug. Conclusion With this standardized and reliable in vitro assay, important S. mansoni developmental stages up to LiS worms can be generated and cultured over an extended period. When exposed to a subset of the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection, 3 compounds yielded a defined anti-schistosomal phenotype on juvenile worms. Translation of activity on perfused adult S. mansoni worms was achieved only for perhexiline (a prophylactic antianginal agent) and astemizole (an antihistaminic drug).

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Identification of annotated bioactive molecules that impair motility of the blood fluke Schistosoma mansoni

Cited by 15 publications

References 80 publications

Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation

Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence

Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium

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