Using ChEMBL to Complement Schistosome Drug Discovery.

Area of Science:

• Neglected tropical diseases research
• Drug discovery and development
• Parasitology

Background:

• Schistosomiasis remains a major global health burden, primarily managed through praziquantel chemotherapy.
• The emergence of praziquantel-resistant schistosomes poses a significant threat to current control strategies.
• Accelerating the discovery of new anti-schistosomal drugs is crucial.

Purpose of the Study:

• To outline a strategy for accelerating early-stage schistosome drug discovery by integrating schistosome-specific resources with the ChEMBL database.
• To identify novel chemical compounds with anti-schistosomal activity.

Main Methods:

• Leveraging functional genomics, bioinformatics, cheminformatics, and phenotypic data.
• Utilizing the open-access drug discovery database ChEMBL.
• Screening compounds for ex vivo anti-schistosomula and adult schistosome activity, and assessing egg production inhibition.

Main Results:

• Seven compounds, including fimepinostat, trichostatin A, NVP-BEP800, luminespib, epoxomicin, CGP60474, and staurosporine, showed sub-micromolar anti-schistosomula potency.
• Epoxomicin, CGP60474, and staurosporine demonstrated potent, fast-acting effects on adult schistosomes and inhibited egg production.
• ChEMBL toxicity data supported CGP60474, luminespib, and TAE684 as promising novel anti-schistosomal candidates.

Conclusions:

• The integrated approach effectively accelerates the identification and preclinical progression of new anti-schistosomal drug candidates.
• This strategy is vital for replenishing the limited pipeline of advanced anti-schistosomal compounds.
• Novel compounds like CGP60474 show significant potential for combating praziquantel-resistant schistosomiasis.