Targeting Echinococcus multilocularis PIM kinase for improving anti-parasitic chemotherapy

by Selleckchem | Mar 18 2023

Background: The potentially lethal zoonosis alveolar echinococcosis (AE) is caused by the metacestode larval stage of the tapeworm Echinococcus multilocularis. Current AE treatment options are limited and rely on surgery as well as on chemotherapy involving benzimidazoles (BZ). BZ treatment, however, is mostly parasitostatic only, must be given for prolonged time periods, and is associated with adverse side effects. Novel treatment options are thus urgently needed.

Methodology/principal findings: By applying a broad range of kinase inhibitors to E. multilocularis stem cell cultures we identified the proto-oncogene PIM kinase as a promising target for anti-AE chemotherapy. The gene encoding the respective E. multilocularis ortholog, EmPim, was characterized and in situ hybridization assays indicated its expression in parasite stem cells. By yeast two-hybrid assays we demonstrate interaction of EmPim with E. multilocularis CDC25, indicating an involvement of EmPim in parasite cell cycle regulation. Small molecule compounds SGI-1776 and CX-6258, originally found to effectively inhibit human PIM kinases, exhibited detrimental effects on in vitro cultured parasite metacestode vesicles and prevented the formation of mature vesicles from parasite stem cell cultures. To improve compound specificity for EmPim, we applied a high throughput in silico modelling approach, leading to the identification of compound Z196138710. When applied to in vitro cultured metacestode vesicles and parasite cell cultures, Z196138710 proved equally detrimental as SGI-1776 and CX-6258 but displayed significantly reduced toxicity towards human HEK293T and HepG2 cells.

Conclusions/significance: Repurposing of kinase inhibitors initially designed to affect mammalian kinases for helminth disease treatment is often hampered by adverse side effects of respective compounds on human cells. Here we demonstrate the utility of high throughput in silico approaches to design small molecule compounds of higher specificity for parasite cells. We propose EmPim as a promising target for respective approaches towards AE treatment.

Comments：

The study aimed to identify potential targets for the development of novel treatments for alveolar echinococcosis (AE), a potentially lethal disease caused by the tapeworm Echinococcus multilocularis. The current treatment options for AE are limited and have significant adverse effects. The researchers applied a range of kinase inhibitors to E. multilocularis stem cell cultures to identify potential targets for anti-AE chemotherapy. They found that the proto-oncogene PIM kinase could be a promising target for AE treatment.

The researchers characterized the gene encoding the E. multilocularis ortholog of PIM kinase, EmPim, and demonstrated its expression in parasite stem cells. They also showed that EmPim interacts with E. multilocularis CDC25, indicating its involvement in parasite cell cycle regulation. The researchers identified two small molecule compounds, SGI-1776 and CX-6258, which effectively inhibited human PIM kinases and had detrimental effects on in vitro cultured parasite metacestode vesicles. These compounds also prevented the formation of mature vesicles from parasite stem cell cultures.

To improve the specificity of the compounds for EmPim, the researchers applied a high throughput in silico modelling approach and identified compound Z196138710. This compound proved equally detrimental to in vitro cultured metacestode vesicles and parasite cell cultures as SGI-1776 and CX-6258 but displayed significantly reduced toxicity towards human HEK293T and HepG2 cells.

Overall, the study demonstrates the potential utility of repurposing kinase inhibitors for helminth disease treatment and the use of high throughput in silico approaches to design small molecule compounds of higher specificity for parasite cells. The researchers propose EmPim as a promising target for the development of novel treatments for AE.