Drug discovery against malaria parasite: drug repositioning strategy

Drug discovery;Malaria

No, Joo Hwan

关键词: Drug discovery;    Malaria;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/26307/No_JooHwan.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Malaria, caused by Plasmodium spp., causes ~1 million deaths each year and there areever present problems due to drug resistance. In this work, I used drug-repositioningstrategy with bisphosphonates to discover a lead that is active against malaria in vivo. Thedevelopmental procedures include, in vitro high throughput screening, x-raycrystallography and other biophysical techniques. First, a computational method wasdeveloped to elucidate the target of bisphosphonate in malaria parasite and, second, inhousesynthesized library of prenyl synthase inhibitors was used to find the lead, ananalog of zoledronate, against the parasite, which the x-ray structure bound to targetenzyme, farnesyl diphosphate synthase (FPPS), was solved. Also, the effect of lipophilicbisphosphonate against liver stage malaria parasite was investigated. Lastly, I studied themechanism and inhibition of IspH, the last enzyme of nonmevalonate pathway, fordiscovery of a novel target for infectious disease.