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Biochemical Characterization of FIKK Kinase from Cryptosporidium Parvum and Discovery of Potent Inhibitors

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Biochemical Characterization of FIKK Kinase from Cryptosporidium Parvum and Discovery of Potent Inhibitors Biochemical Characterization of FIKK Kinase from Cryptosporidium parvum and Discovery of Potent Inhibitors. by Khan Tanjid Osman A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Molecular Genetics University of Toronto © Copyright by Khan Tanjid Osman 2016 Biochemical Characterization of FIKK Kinase from Cryptosporidium parvum and Discovery of Potent Inhibitors. Khan Tanjid Osman Doctor of Philosophy Molecular Genetics University of Toronto 2016 Abstract Cryptosporidium parasites cause serious human and animal diseases and affect millions of children worldwide. Drug discovery attempts against the parasites are insufficient and new drug targets are necessary. C. parvum harbors some unique protein kinases including one called FIKK kinase. FIKKs are parasite-specific protein kinases with distinctive sequence motifs and restricted to phylum Apicomplexa. The biochemistry and biology of the evolutionarily conserved members of the FIKK family have not been elucidated before this project. I explored the biochemical nature of the most conserved FIKK members in C. parvum and malaria causing P. falciparum, known as CpFIKK and PfFIKK8, respectively. I have identified the soluble domain boundary of the proteins and their substrate preferences, and characterized their activity in vitro. FIKKs need a ~40 residue extension to the predicted kinase domain to be soluble. They prefer Ser as phosphoacceptor residue flanked by Arg at the -3 and +3 positions in the substrate. Because their biological roles have not been completely elucidated, potent, selective and cell ii permeable inhibitors would be useful to understand the biological roles of FIKKs in parasites. Here, I report the first Cryptosporidium FIKK (CpFIKK) inhibitor and its selectivity profile. I systematically explored the structure activity relationship for CpFIKK inhibition and for selectivity against CpCDPK1. I identified 4b as a potent (IC50 = 0.2 nM) inhibitor of CpFIKK catalytic activity, and confirmed CpFIKK binding using a thermal melt assay. Minor variations of inhibitor structure led to significant change in selectivity profiles against CpCDPK1 and identified CpCDPK1 selective as well as dually acting C. parvum FIKK-CDPK1 inhibitors from the same structural class of compounds. I evaluated these CpFIKK inhibitors for inhibition of parasite growth in vitro. The observed effect in parasite growth did not correlate with CpFIKK inhibition. iii Dedication To my parents Dr. Khan Towhid Osman and Ms. Taslima Begum From whom I inherited my set of kinase genes iv Acknowledgments First and foremost, I like to thank my advisor Dr. Aled M. Edwards. It has been a privilege to work under his supervision. His tremendous support, endless patience, sincerity and guidance were crucial for the fulfillment of my project. His views on science, enthusiasm and wonderful ideas motivated me to take risk and challenge myself, helped me to design experiments and forced me to think outside the box. I appreciate his contributions of time, advice and funding to make my research productive, fun and stimulating. I count myself extremely fortunate to be supervised by such an outstanding science leader and one of the frontline advocates of open access science. Most of my research work was conducted in the Structural Parasitology laboratory within the Structural Genomics Consortium (SGC), Toronto (thesgc.org). I would like to thank the principal investigator of the group and my co-supervisor Dr. Raymond Hui for his excellent support. Working in a super-productive lab under his leadership helped my research tremendously. I am greatly thankful for the time, patience, effort and ideas he contributed for my project. I would also like to extend my sincere gratitude to the supervisory committee members Drs. Frank Sicheri and Scott Gray-Owen for their suggestions, ideas and time that led this research towards right direction. I am specially grateful to Dr. Vijayaratnam Santhakumar from ChemNet, SGC, for leading the inhibitor compound discovery project. Lab members of Structural Parasitology helped me immensely in numerous ways. Special thanks to Diego Lovato, Linda Lin, Mehrnaz Amani, Ashley Hutchinson, Majida El Bakkhouri, Tania Hills, David Hou, Wei Qiu, Maria Mangos, Dunquan Jiang and Verena Brand for their tremendous support. I am grateful to the members from other groups of SGC for their assistance, specially to Peter Loppnau for cloning, Ashley Hutchinson for protein expression, Guillermo Senisterra and Abdellah Allali-Hassani for biophysical and biochemical assays, and Mani Ravichandran for crystallography. I would like to extend my gratitude to Greg Brothers, Merilyn Pereira and Rebecca Clare of SGC for their kind support in administrative matters. This work was aided by several collaborations and I would like to thank all of the awesome collaborators: laboratories of Dr. Benjamin Turk from Yale University, Dr. Mark Lautens from University of Toronto, Dr. Dana Mordue from New York Medical College, Christopher Huston v from University of Vermont, Dr. Serge Muyldermans from VIB Structural Biology Research Center, Dr. Bill Zuercher from University of North Carolina. Particularly, I would like to thank Hua Jane Lou from Turk lab for peptide library screening, to Rajiv S. Jumani from Huston lab for performing Cryptosporidium parvum inhibition assays, to Juntao Ye from Lautens lab for synthesizing inhibitor compounds and to Odaelys Walwyn from Mordue lab for performing Toxoplasma gondii inhibition assays. During the period of my PhD program, I have visited many labs to learn different techniques on cell biology and genetics experiments and I want to express my sincere gratitude to Dr. John Parkinson from SickKids, University of Toronto (for T. gondii cellular and inhibition assays), Dr. David Sibley from Washington University in St. Louis (for T. gondii genetic manipulation techniques) and Dr. Momar Ndao (for C. parvum cellular and inhibition assays) for their kind permission to work in their labs. This research was funded by different academic and industry partners through the SGC. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and the Wellcome Trust. I would like to thank all of the funders for providing me with this opportunity. Last but not least, I want to thank my family members, without whom this work would not be possible. My parents encouraged and motivated me to pursue the PhD degree. Finally, I would like to thank my wonderful wife Ms. Sadiah Mussarrat for her support, love and care. Her comfort, guidance and assistance were indispensable for me throughout this work. vi Table of Contents Contents Dedication ...................................................................................................................................... iv Acknowledgments............................................................................................................................v Table of Contents .......................................................................................................................... vii List of Tables ...................................................................................................................................x List of Figures ............................................................................................................................... xii Chapter 1 ..........................................................................................................................................1 1 Introduction .................................................................................................................................1 1.1 Cryptosporidium causes serious human and animal diseases ..............................................1 1.2 Epidemiology, taxonomy and life cycle of C. parvum ........................................................2 1.3 Drug discovery efforts against Cryptosporidium and other apicomplexans ........................5 1.4 Targeting protein kinases in parasites for new drug discovery: learning from the past ......7 1.4.1 Ligand-substrate interaction in protein kinases .......................................................8 1.4.2 Known inhibitors of parasite kinases .....................................................................10 1.5 The Cryptosporidium kinome: a hub of unique kinases ....................................................11 1.6 The FIKK kinase family ....................................................................................................13 1.6.1 Number of FIKK members in apicomplexan genomes .........................................13 1.6.2 Domain architectures and known biological functions of FIKKs .........................14 1.6.3 Lone FIKKs are orthologous to FIKK8 from P. falciparum .................................19 1.6.4 FIKKs contain putatively active kinase domains...................................................19 1.6.5 The FIKK kinase domains share some features of atypical protein kinases ..........21 1.6.6 Evidence for catalytically active FIKKs ................................................................23
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