<p dir="ltr">Human babesiosis is a malaria-like, tick-borne infectious disease of major public health importance with a global distribution. Babesiosis is caused by intraerythrocytic, apicomplexan parasites of the genus Babesia. In the United States, human babesiosis is primarily caused by Babesia microti and Babesia duncani. Of these parasites, B. duncani infection is lethal to susceptible patients. Current treatment for babesiosis includes either the synergistic use of atovaquone and azithromycin or the combination of clindamycin and quinine. However, the side effects and the resistance posed by these parasites called for alternative approaches for the treatment of human babesiosis. Parasite-derived proteases play several functions in the context of parasitic lifestyle and regulate basic biological processes including cell death, cell progression and cell migration. We hypothesized that proteases are promising class of drug targets in Babesia parasites. Using the SYBR-Green assay, we screened a protease inhibitor library consists of 160 compounds against B. duncani in vitro culture at 50µM and identified 13 preliminary hits. Additionally, dose response assays of hit compounds against <i>B. duncani</i> and <i>B. microti</i> in vitro cultures identified 5 compounds as effective inhibitors against parasite growth. Of these 5 compounds, we chose ixazomib, a proteasome inhibitor as a potential drug for further studies based on its lower IC50 of 58nM as well as a higher therapeutic index as compared to other hit compounds. We demonstrated that in a mouse model infected with <i>target,</i>, the most effective inhibitor, the prodrug of ixazomib at a low dose of 2.5mg/kg lowers parasite proliferation without causing any adverse effects in animals. Thus, our studies suggest that Babesia proteasome may be an important drug target, and ixazomib may be a potential compound that may be used for the treatment of human babesiosis.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/25668702 |
| Date | 23 April 2024 |
| Creators | Temitope S Aderanti (18423210) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/TARGETING_PROTEASOME_IN_BABESIA_PARASITES_TO_COMBAT_HUMAN_BABESIOSIS/25668702 |
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