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Mechanistic Studies of Anti-Leishmanial Arylimidamides

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Mechanistic Studies of Anti-Leishmanial Arylimidamides MECHANISTIC STUDIES OF ANTI-LEISHMANIAL ARYLIMIDAMIDES DISSERTATION Presented in Partial Fulfillments of the Requirements for the Degree Doctor of Philosophy from the Graduate School of The Ohio State University By Trupti Pandharkar, M.S. ****** Graduate Program in Medicinal and Pharmaceutical Chemistry The Ohio State University 2012 Dissertation Committee: Karl A. Werbovetz, Ph.D., Advisor Esperanza Carcache de Blanco, Ph.D. Mark E. Drew, Ph.D. Juan D. Alfonzo, PhD. Copyright by Trupti Pandharkar 2012 ABSTRACT Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the genus Leishmania . With the estimated global incidences of 0.7 to 1.2 million for CL cases and 0.2 to 0.4 million VL cases cases per year, leishmaniasis is estimated to cause the ninth largest burden of disease. In the absence of effective treatment, visceral leishmaniasis is most often fatal and cutaneous and other forms of this disease often result in severe disfigurement and can be debilitating. Given the issues with existing treatment options, like toxicity, prohibitive cost and loss of effectiveness due to emergence of drug resistant strains, the need for the new drugs is urgent. With the mission to develop cheaper, safer and more efficacious drugs, the Consortium for Parasitic Drug Development (CPDD) has synthesized and evaluated series of diamidine analogs for their anti-parasitic activity against several pathogens including Leishmania. Medicinal chemistry efforts to improve the efficacy of diamidines resulted in discovery of new class of molecules called ‘arylimidamides (AIAs)’ with extraordinary activity, especially against intracellular pathogens like T. cruzi and Leishmania . The anti- leishmanial efficacy of an AIA, DB766 (2,5-bis[2-(2-propoxy)-4-(2- ii pyridylimino)aminophenyl]furan hydrochloride) that displayed outstanding activity against the intracellular form of Leishmania donovani [IC 50 = 0.036 µM] and oral efficacy in murine and hamster models of visceral leishmaniasis [71% and 89% reduction in liver parasitemia at 100 mg/kg/day × 5, respectively] was recently reported. Despite intensive lead optimization efforts that permitted exhaustive analysis of the AIA structure activity relationship, attempts to improve the efficacy of AIAs have met with limited success. The lack of knowledge about the parasite drug target and the host toxicity mechanism has precluded further pre-clinical development of AIAs. In the present study, we employed three different approaches, 1) a 2 dimensional difference in gel electrophoresis-mass spectrometry (2D-DiGE-MS) assisted comparative proteomics analysis to study changes in the Leishmania proteome post-treatment with the lead AIA- DB766, 2) transmission electron microscopy to study the ultrastructural alterations caused by DB766 treatment in Leishmania and 3) generation and characterization of a Leishmania cell line that is over 10-fold resistant to DB766 through stepwise increases in the concentration of the compound to identify the target and understand the anti- leishmanial mechanism of action of AIAs to facilitate future anti-leishmanial drug discovery efforts. The DiGE approach used in this study led to the identification of 19 proteins that were differentially modulated in DB766 treated Leishmania. Most of the downregulated proteins like RNA helicase, mitochondrial tryparedoxin peroxidase (mTXNPx), HSP60, ATP synthase and ATPase were nuclear encoded mitochondrial proteins and four iii upregulated proteins corresponding to HSP60 were mitochondrial precursors, leading to the evaluation and confirmation of mitochondrial involvement in response to DB766 treatment in Leishmania . However, in the absence of the specific target information and considering the fact that mitochondrial involvement could be a secondary event downstream of a primary target, more detailed investigation employing other approaches was undertaken. Comparison of the ultrastructural effects of AIAs with the diamidine DB1111 in Leishmania donovani axenic amastigotes indicated that, unlike DB1111, DB766 treatment did not result in any change in the mitochondrial morphology of these parasites. However, dramatic ultrastructural alterations were noted in other organelles. The similarities in the ultrastructural profile induced by DB766 to those produced by sterol biosynthesis inhibitors and protease inhibitors in Leishmania led to evaluation of hypotheses that AIAs act via protease inhibition and/or disturbances in sterol metabolism in Leishmania . In fluoregenic serine protease substrate based assays, DB766 failed to show marked inhibition of oligopeptidase B like enzyme activity in Leishmania lysates, leading to cessation of its pursuit as a target of the AIAs. However, GC-MS analysis of Leishmania sterols indicated important changes in the sterol profile of DB766 treated Leishmania, consistent with the ‘disturbances in sterol metabolism’ hypothesis . In an attempt to identify mutations that cause resistance and in the hope of obtaining additional mechanistic information, a L. donovani axenic amastigotes cell line over 10- iv fold resistant to DB766 was developed and characterized. In vitro susceptibility assays revealed that these DB766 resistant parasites (766R) are hypersensitive to miltefosine (over 2-fold more sensitive) and anti-fungal azoles (over 1000-fold more sensitive). Systematic studies to test the hypothesis that resistance to DB766 is associated with perturbations in Leishmania sterol metabolism and enzymes in the sterol biosynthetic pathway were undertaken. Western blot analysis of 766R parasites indicated dramatically reduced expression of CYP5122A1, a recently identified cytochrome P450 associated with ergosterol metabolism in Leishmania , in the DB766 resistant parasites. GC-MS analysis of sterols extracted from DB766 sensitive and resistant parasites indicated that the reduced expression of CYP5122A1 was associated with changes in the levels of sterol intermediates without affecting the ergosterol content. Susceptibility assays demonstrated that CYP5122A1 single knockout (HKO) Leishmania donovani promastigotes are significantly less susceptible to DB766 and more susceptible to ketoconazole than their wild type counterparts, consistent with the observations in DB766 resistant parasites. Our studies demonstrate that 1) DB766 disrupts sterol metabolism in Leishmania and synergizes the anti-leishmanial activity of posaconazole 2) CYP5122A1 plays an important role in governing susceptibility and resistance to DB766 in this parasite, and 3) CYP5122A1 also modulates the susceptibility of Leishmania to antifungal azoles. These results support our hypothesis that DB766 and other AIAs disrupt sterol metabolism by targeting CYP5122A1, in Leishmania. v DEDICATED TO MY DAUGHTER AMBAR, HUSBAND ROHIT TIWARI AND MY PARENTS, DILIP AND SANDHYA PANDHARKAR vi ACKNOWLEDGMENTS The pursuit of my PhD has been a long journey. It wouldn’t have been possible for me to complete my studies without invaluable help and support from numerous people during this journey. Beginning with my advisor, I would like to give my special thanks to Karl Werbovetz for providing me with intellectual insights, guidance and encouragement throughout my graduate career. If not for his patience with me, faith in me, flexibility, genuine care and concern, I would not have been able to attend to demands of life outside the scientific career. He has never judged me and has always gently encouraged me, knowing that I need to juggle priorities. I am also grateful to Richard Burchmore, University of Glasgow, UK, for his help and discussion with the initial proteomics experiment. I also sincerely appreciate Frederick Buckner and members of his group at University of Washington, Seattle, for their help with the GC-MS analysis of Leishmania sterol samples and for providing me anti-CYP51 antibody for Western blot analysis. I thank Chandrima Shaha and members of her group at National Institute of Immunology, India for their help with drug susceptibility studies with genetically modified Leishmania cell line and also for providing me with anti- CYP5122A1 antibody for Western blot analysis and CYP5122A1 expression plasmid for future studies. I am also grateful to Mark Drew and members of his group for helping me with flow cytometry, Robert Curley for helping with GC instrumentation, Werner Tjarks and members of his group for helping me with HPLC instrumentation and Thomas Schmittgen and members of his group for helping me with Real Time PCR assays. vii I am incredibly grateful for the financial support from the Bill and Melinda Gates Foundation. I am also grateful for scientific feedbacks and invaluable insights from members of my academic committee: Pui-Kai (Tom) Li, Esperanza Carcache de Blanco, Mark Drew and Juan Alfonzo. I also extend my heartfelt gratitude to my fellow graduate students and post docs in both Werbovetz and Li labs, especially Xiaohua, Carolyn, Sihui, Molla, Julian, Shanshan, Jason, Bulbul, Deepak, Nick, Som, Jonathan and Justin. Their presence helped to lighten my stress and keep the lab environment fun and sane. I have a learned a lot from all of them during the humorous marathon discussions that we had on topics like science, politics, culture, spirituality and many more. I also give my special thanks to Swati Dhar and Dakshayini Rao for playing the part of a friend and confidante and providing support and care. In addition, I give my sincere thanks to people for their assistance with some of the experiments described in this dissertation:
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