Targeting the process of attachment in Giardia lamblia pathogenesis : a new approach in Giardia drug discovery
Walls, Colleen Daun.
Thesis (Ph.D.)--Georgetown University, 2010.; Includes bibliographical references.; Text (Electronic thesis) in PDF format. Giardia lamblia is one of the most prevalent intestinal parasites worldwide and is a significant contributor to diarrheal diseases. Treatment of Giardia has proven to be difficult as there is no vaccine and the arsenal of chemotherapeutics is limited. Challenges regarding current treatments include high recurrence rates, frequency and severity of side effects, and reports of resistance and contraindications. These challenges have demonstrated a clear need to develop novel chemotherapeutics.; Parasite attachment to the epithelial lining of the small intestine is a critical step in initiating and maintaining an infection, making it an appealing drug target. Unfortunately, our ability to develop novel drugs that specifically target attachment has been hindered by our lack of knowledge regarding the mechanism, and our poor understanding of the cellular machinery involved in attachment is in turn largely due to a lack of research tools.; Here, we have devised a top-down phenotypic high-throughput inhibitor screen that targets parasite attachment. The significance of our top-down approach is two-fold; (1) identifying compounds that inhibit parasite attachment may be useful in identifying and developing novel drug candidates for the treatment of giardiasis, and (2) identifying compounds that will broaden our understanding of the process of attachment will ultimately allow us to identify a larger range of novel drug targets.; Here, we have screened 1,978 compounds from the NCI Diversity Set I, and have identified seven top lead drug candidates that significantly inhibit attachment between 5-10uM, without affecting IEC-6 host cells at a higher concentration (50uM). Currently these compounds are under review for U.S. patent rights as prospective lead compounds for chemotherapeutic development.; To further gain insights on the mechanism of attachment, we have conducted videomicroscopy of parasite morphology and behavior in response to our top lead hits. We defined 3 phenotypic categories: compounds that disrupted parasite morphology; compounds that did not affect gross parasite morphology but that caused flagellar paralysis; and most relevant, compounds that did not affect gross parasite morphology or activity, but that prevented attachment. Compounds that appear to specifically inhibit attachment are promising tools for future identification of the cellular machinery involved in Giardia attachment.
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