Old drug repurposing for neglected disease: Pyronaridine as a promising candidate for the treatment of Echinococcus granulosus infections

Abstract

Background: Cystic echinococcosis (CE), a condition caused by the larval stage of the dog tapeworm Echinococcus granulosus sensu stricto, is a globally distributed zoonotic disease. Current treatment options for CE are limited, and an effective and safe anti-echinococcal drug is urgently required. Methods: Drug repurposing strategy was employed to identify new therapeutic agents against echinococcal cysts. An in vitro protoscolicidal assay along with in vivo murine models was applied in the drug screening. A microinjection procedure was employed to mimic the clinical PAIR (puncture, aspiration, injection and reaspiration) technique to evaluate the potential application of the candidate drug in clinical practice. Findings: We repurposed pyronaridine, an approved antimalarial drug, for the treatment of CE. Following a three-dose intraperitoneal regimen (57 mg/kg, q.d. for 3 days), pyronaridine caused 100% cyst mortality. Oral administration of pyronaridine at 57 mg/kg, q.d. for 30 days significantly reduced the parasitic burden in the pre-infected mice compared with albendazole group (p < 0.001). Using a microinjection of drug into cysts, pyronaridine (200 mM) showed highly effective in term of inhibition of cyst growth (p < 0.05, compared with saline group). Pharmacokinetic analysis revealed that pyronaridine was highly distributed in the liver and lungs, the most affected organs of CE. Function analysis showed that pyronaridine inhibited the activity of topoisomerase I (IC 50 = 209.7 § 1.1 mM). In addition, classical apoptotic hallmarks, including DNA fragmentation and caspase activation, were triggered. Interpretation: Given its approved clinical safety, the repurposing of pyronaridine offers a rapidly translational option for treating CE including PAIR.

Transcriptome analysis uncovers the key pathways and candidate genes related to the treatment of Echinococcus granulosus protoscoleces with the repurposed drug pyronaridine

“…PND killed 100 % of the cysts in a mouse infection model by intraperitoneal injection at 57 mg/kg/day for three days. When administered orally with a regimen of 57 mg/kg/day × 30 days, it produced 90.7 % cyst mortality, showing that PND is much more effective than albendazole (22.2 % cyst mortality at 50 mg/kg/day), the only anti-CE drug recommended by WHO [ 8 ]. However, the anti-parasitic mechanism of PND remains unclear.…”

“…After three washes with PBS, the PSCs were cultured in RPMI 1640 culture medium (Gibco, cat#31,800,022) containing 10 % fetal bovine serum (Gibco, cat#10,099,141 C) and antibiotics (100 U/mL penicillin and 100 µg/mL streptomycin, Gibco, cat#15140-122) in a CO 2 (5 %) incubator at 37 °C. PND tetraphosphate was synthesized in-house [ 8 ] and dissolved in PBS to prepare a drug solution. Viable PSCs were aliquoted in a 24-well plate with each well-containing 2,100 PSCs.…”

“…Among current CE treatment options, anti-parasitic drug therapy is widely used for most clinical cases [ 6 , 7 ]. Recently, we repurposed an approved anti-malarial drug pyronaridine (PND) as a promising candidate for CE treatment [ 8 ]. Oral administration of PND showed high concentrations of the drug in the liver and lungs, which are the most affected organs in CE.…”

Pyronaridine: An update of its pharmacological activities and mechanisms of action

“…The antiparasitic activity was attributed to a druginduced inhibition of the parasite topoisomerase 1 enzyme. [85] There are probably other targets because PYR is not a highly effective Topo1 inhibitor; it principally targets Topo 2. Nevertheless, these new data are very encouraging and confirm that the repurposing of PYR as an antiparasitic or an antifungal agent is worth to be considered, as it is the case with other acridines.…”

Gut Flora Mediated Mouse Metabolic Health Risk Caused by Dietary Exposure of Acetamiprid and Tebuconazole

“…Liver is the largest digestive gland in the body and the main metabolic organ [22,23], and serum biochemistry analysis is an effective method to evaluate liver function in clinical diagnosis [24]. In this work, liver function was investigated and evaluated using related indices ( Fig.…”