Mitochondria as a Potential Target for the Development of Prophylactic and Therapeutic Drugs against Schistosoma mansoni Infection

Abstract

Emergence of parasites resistant to praziquantel, the only therapeutic agent, and its ineffectiveness as a prophylactic agent (inactive against the migratory/juvenile Schistosoma mansoni ), makes the development of new antischistosomal drugs urgent. The parasite’s mitochondrion is an attractive target for drug development because this organelle is essential for survival throughout the parasite’s life cycle. We investigated the effects of 116 compounds against Schistosoma mansoni cercariae motility that have been reported to affect mitochondria-related processes in other organisms. Next, eight compounds plus two controls (mefloquine and praziquantel) were selected and assayed against motility of schistosomula ( in vitro ) and adults ( ex vivo ). Prophylactic and therapeutic assays were performed using infected mouse models. Inhibition of oxygen consumption rate (OCR) was assayed using Seahorse XFe24 Analyzer. All selected compounds showed excellent prophylactic activity, reducing the worm burden in the lungs to less than 15% that obtained in the vehicle control. Notably, ascofuranone showed the highest activity with a 98% reduction of the worm burden, suggesting the potential for development of ascofuranone as a prophylactic agent. The worm burden of infected mice with S. mansoni at the adult stage was reduced by more than 50% in mice treated with mefloquine, nitazoxanide, amiodarone, ascofuranone, pyrvinium pamoate, or plumbagin. Moreover, adult mitochondrial OCR was severely inhibited by ascofuranone, atovaquone, and nitazoxanide, while pyrvinium pamoate inhibited both mitochondrial and non-mitochondrial OCRs. These results demonstrate that the mitochondria of S. mansoni are feasible target for drug development.

Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

“…Although the use of PP as an anthelminthic has dwindled over the years, since the early 2000s, interest in PP has surged due to its potential utilization to target other diseases-causing organisms at every level from viral [ 27 , 28 ] through bacterial [ 29 , 30 , 31 ], plasmodium [ 32 ], and fungi [ 33 , 34 , 35 ] to multicellular organisms [ 36 ] ( Figure 2 ). PP has also shown significant potential in multiple disease types for the ability to reduce toxicity, promote wound repair, and inhibit fibrotic tissue development [ 37 , 38 , 39 , 40 , 41 , 42 ].…”

Toxic Effects of Penetrating Cations

“…Similar to other clinically used penetrating cations, its mitochondrial localization and targeting are well documented [33]. In particular, it has been shown that pyrvinium inhibits mitochondrial respiration in a parasitic worm [34]. Its mitochondrial accumulation is also responsible for its activity against pathogenic fungi such as Candida auris [35] and Aspergillus fumigatus [36].…”

New Uses for Old Drugs and Their Application in Helminthology

“…In contrast, this compound caused a significant reduction in worm and egg burden in early infection (>50%) [48]. Similarly, Talaam et al, (2021), evaluated the possible effect of amiodarone against S. mansoni. In this experiment, amiodarone showed complete inhibition of cercaria motility after 18 hours.…”

“…In the case of schistosomula, after 24 hours with amiodarone, the inhibition of motility was complete. In adult parasites, amiodarone inhibited the motility after 20 hours of incubation was not complete, providing mean motility scores of 0.3 and 1.0 for the male and female, respectively [49]. In in vivo experiments, mice were prophylactically treated with amiodarone (50 mg/kg) by 4 days of once-daily intraperitoneal injection, starting 1 day prior to infection, and then euthanized six days postinfection to recover the schistosomula from the lungs.…”

“…The results show a worm burden reduced to 14.7%. In the case of therapeutic treatment, the mice at week six after infection were treated intraperitoneally with amiodarone (50 mg/kg) for 4 days, and subsequently, they were sacrificed 14 days after the last treatment, the parasite load showed a decrease to 29.2% [49].…”