The Schistosoma mansoni Phosphatome as a Frontier for Antischistosomal Drug Discovery: Molecular Functions, Target Validation and Therapeutic Perspectives

Schistosomiasis remains a major neglected tropical disease, affecting millions of people worldwide and causing substantial morbidity, particularly in endemic communities. Despite decades of control efforts, treatment still depends largely on praziquantel. Although the drug is highly effective against adult schistosomes, its activity against immature developmental stages is reduced, and it does not prevent reinfection. These limitations highlight the need for alternative therapeutic strategies. Protein phosphatases, which counterbalance protein kinases by regulating reversible phosphorylation, represent an important but comparatively neglected part of the Schistosoma mansoni drug-discovery landscape. The S. mansoni phosphatome includes diverse phosphatase families, such as serine/threonine phosphatases, protein tyrosine phosphatases, dual-specificity phosphatases, and metal-dependent phosphatases, with potential roles in signalling, development, metabolism, reproduction, stress responses, and parasite survival. The importance of phosphorylation-dependent regulation, together with the identification of essential phosphatases through functional genomic approaches, supports their consideration as potential therapeutic targets. Their catalytic domains, structural features, parasite-specific characteristics, and essential biological functions may offer opportunities for selective pharmacological intervention. Emerging approaches that combine RNA interference, phosphoproteomics, comparative genomics, structural bioinformatics, virtual screening, phenotypic screening, and biochemical target-engagement assays are making systematic target identification and validation in S. mansoni increasingly feasible. This review therefore examines the molecular functions and biological significance of the S. mansoni phosphatome, evaluates the evidence for phosphatase target validation and druggability, and discusses emerging strategies for inhibitor discovery. Finally, a translational framework linking phosphatase prioritisation, genetic and biochemical validation, structure-guided discovery, selective inhibitor development, and preclinical evaluation is proposed to help advance phosphatases from neglected regulatory enzymes to validated antischistosomal drug targets.