Drug development targeting the mitochondrial respiratory chain of Sparganum proliferum: Initial biochemical and drug discovery insights into the enigmatic helminth parasite.

Sparganum proliferum undergoes asexual proliferation within the human host, leading to multiorgan failure and death. Currently, no effective treatment is available. Long considered mysterious, the natural host and transmission route remain unidentified, hindering preventive measures. Furthermore, owing to its extreme rarity, biochemical research and drug development have been neglected. This study investigated mitochondrial function and screened for compounds targeting this parasite. The parasite showed activity of mitochondrial complexes I-IV and NADH-fumarate reductase, indicating a hybrid respiratory chain that supports both aerobic and anaerobic respiration. Quinone-binding site inhibitors showed inhibitory activity against the respiratory chain. Ascofuranone derivatives acted as dual inhibitors of complexes II and III. The antimalarial drug atovaquone inhibited complex III at a very low concentration (IC₅₀ 2.2 nM). IACS-010759 potently inhibited complex I (IC₅₀ 16.1 nM), causing worm body swelling, surface destruction, and mitochondrial morphological changes in culture assays. Further investigation of the mitochondrial respiratory chain of S. proliferum to develop targeted candidate drugs is warranted.