Publication Date

8-2015

Date of Final Oral Examination (Defense)

6-19-2015

Type of Culminating Activity

Thesis

Degree Title

Master of Science in Chemistry

Department

Chemistry

Supervisory Committee Chair

Kenneth A. Cornell, Ph.D.

Supervisory Committee Member

Eric Brown, Ph.D.

Supervisory Committee Member

Kristen Mitchell, Ph.D.

Abstract

The parasitic protozoa Giardia intestinalis and Entamoeba histolytica are major health concerns and responsible for hundreds of millions of cases of intestinal disease per year. Strains of both parasites have been discovered that show resistance to metronidazole, the most prevalent treatment for these pathogens. Thus, there is a need to identify new drugs and drug targets to combat the growing threat of drug resistant parasites. The parasite enzyme methylthioadenosine nucleosidase (MTN) is one such potential target. Traditional drug development processes take almost a decade and hundreds of millions of dollars to complete. In an effort to shorten that timeline and reduce development costs, the drugs tested in this study were found by in silico screening of a drug library containing thousands of small molecules to identify a subset of compounds that showed theoretical high binding affinities to the E. coli MTN enzyme. Enzymatic screening of the 33 tightest binding drugs yielded four potent inhibitors of E. coli MTN that also showed inhibitory activity against target parasite MTNs. The inhibition profiles of these drugs against parasite MTNs and the human enzyme methylthioadenosine phosphorylase (MTAP) were extensively characterized. The drugs were also tested against live cell cultures of Giardia intestinalis and human cell lines for growth inhibitory activity. The drug 5A (N-(2-furyl methyl)-N'-(4-nitrophenyl)urea) showed an IC50 of 10.8 µM against Giardia intestinalis cultures, while exhibiting an IC50 of over 100 µM against human cells. These results suggest that the MTN inhibitors identified in this work are potential lead compounds for further development, and that in silico drug screening is an effective strategy for identifying anti-parasitic agents.

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