Project: Discovery of novel treatment options for Giardiasis
Research group: Zoltner
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Deadline is closed
Giardia lamblia is a protist parasite of the gastrointestinal tractwith an estimated 1.2 million cases occurring annually in the US and over 33% of the population in developing countries have a record ofgiardiasis. Given theextremely frequent occurrence and the emergence of nitroimidazole and benzimidazole (the current frontline drugs) resistant Giardia strains, novel therapeutics are highly desirable. We set out to generate novel preclinical candidate drugs applying two strategies:
(1)A cell based approach: In collaboration with our medicinal chemistry collaborator we have identified a piperazine based compound series active against various protist parasites, which also exhibit low micromolar potency against G.lamblia. We aim to improve the potencyin iterative rounds of synthesis of analogs and assessment in a bioluminescence based viability assay.
(2) A a target based approach: We aim to target amitochondrial processing peptidase, which is aknown essential component of the mitochondrial protein import machinery.TheGiardia enzyme is unique among eukaryotes because ithas undergone reductive evolution to function efficientlyas a single monomer, other than its heterodimeric homologs. We will develop an enzymatic assay to identify inhibitors of the recombinant peptidase and assess their ability to kill Giardia. The resulting ‘lead‘ compounds will be subjected to optimization, co-crystallization with the peptidase and mechanism of action studies.
Deadline is closed