P2 receptors as emerging therapeutic targets in neglected parasitic diseases

Despite sustained control efforts, neglected parasitic diseases, such as malaria, leishmaniasis, Chagas disease, schistosomiasis, and toxoplasmosis, continue to exert a substantial global burden, driven by high prevalence, restricted therapeutic options, drug-associated toxicity, and the progressive emergence of resistance.

Accumulating evidence has positioned purinergic signaling as a central regulatory axis in host-parasite interactions, in which P2 receptors are inherently ambiguous, as their signaling can promote either protective or detrimental immune responses depending on the cellular and microenvironmental context. The activation of the P2X7 receptor encourages inflammasome assembly, proinflammatory cytokine release, and microbicidal activity, aiding parasite elimination, though it can also lead to tissue damage in certain scenarios. Moreover, P2Y receptors regulate immune cell recruitment, cell death, and fibrotic responses, thereby influencing infection progression. Altered expression and function of P2 receptors across parasitic diseases highlight their crucial role in pathogenesis and immune regulation.

This review compiles current evidence supporting P2 receptors as viable therapeutic targets and emphasizes their potential to guide the development of safer and more effective interventions against tropical parasitic diseases.