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

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Vejzagić N.; Prodjinotho U.F.; El-Khafif N.; Huang R.; Simeonov A.; Spangenberg T.; da Costa C.P.

Journal: PLoS Neglected Tropical Diseases

Publisher: Public Library of Science

Publication Date: 25 May 2021

Volume / Issue: Volume 15 / Issue 5

Article No.: e0009432

ISSN: 19352727

DOI: 10.1371/journal.pntd.0009432

Scopus: View on Scopus

PubMed: 34033658

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Vejzagić N., Institute for Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany, Center for Global Health, TUM School of Medicine, Technische Universität München, Munich, Germany; Prodjinotho U.F., Institute for Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany, Center for Global Health, TUM School of Medicine, Technische Universität München, Munich, Germany; El-Khafif N., Theodor Bilharz Research Institute, Mahad Al Abhas Al Bahari, Warraq Al Arab, El Warraq, Giza Governorate, Egypt; Huang R., Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, United States; Simeonov A., Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, United States; Spangenberg T., Global Health Institute of Merck, Ares Trading S.A. (a subsidiary of Merck KGaA Darmstadt Germany), Eysins, Switzerland; da Costa C.P., Institute for Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany, Center for Global Health, TUM School of Medicine, Technische Universität München, Munich, Germany

Abstract

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). © 2021, Public Library of Science. All rights reserved.

Keywords

Animals; Astemizole; Drug Evaluation, Preclinical; In Vitro Techniques; Perhexiline; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides; alverine; antiangina pectoris agent; antihistaminic agent; antineoplastic agent; antischistosomal agent; aprindine; berberine; bifemelane; dibenzepin; dilazep; dimethyl sulfoxide; fasoracetam; flupentixol; gallopamil; ifenprodil; nefopam; paraoxon; penicillin derivative; pentobarbital; pizotifen; praziquantel; sanguinarine; sertindole; spiperone; streptomycin; thioproperazine; animal cell; animal experiment; animal tissue; antiprotozoal activity; Article; Biomphalaria glabrata; body height; bright field microscopy; cell structure; cell viability; cercaria; cheminformatics; controlled study; drug screening; granulation tissue; in vitro study; integument; juvenile; lipophilicity; mitochondrion; nonhuman; oocyte maturation; parasite viability; parenchyma; phenotype; prothrombin time; quality control; scanning electron microscopy; schistosomiasis; schistosomulum; transmission electron microscopy; animal; drug effect; growth, development and aging; preclinical study; procedures

Citation Information

Scopus Citations: 3

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