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(CADA) Analogs to Target Signal Peptides

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(CADA) Analogs to Target Signal Peptides University of Nevada, Reno Synthesis & Pharmacokinetic Evaluation of Cyclotriazadisulfonamide (CADA) Analogs to Target Signal Peptides A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry by Dylan E. Jones Prof. Thomas W. Bell/Dissertation Advisor May 2019 THE GRADUATE SCHOOL We recommend that the dissertation prepared under our supervision by DYLAN E. JONES entitled Synthesis and Pharmacokinetic Evaluation of cyclotriazadisulfonamide (CADA) Analogs to Target Signal Peptides be accepted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Thomas W. Bell, Ph.D., Advisor Wesley Chalifoux, Ph.D., Committee Member Ana de Bettencourt-Dias, Ph.D., Committee Member Dylan Kosma, Ph.D., Committee Member Ian Wallace, Ph.D., Graduate School Representative David W. Zeh, Ph.D., Dean, Graduate School May 2019 i Abstract The small molecule cyclotriazadisulfonamide (CADA) was found to down- modulate the expression of the human cluster of differentiation 4 (hCD4) glycoprotein and sortilin through a specific interaction with respective signal peptide (SP), a short chain of amino acids that initiates a highly conserved biochemical process called cotranslational translocation. The SP is an unprecedented target in modulating protein expression. Since each protein expressed through cotranslational translocation has a unique SP, small molecules may potentially be designed to target individual SPs and modulate protein expression with high specificity. The goals of this research were to synthesize CADA analogs to study the interactions between CADA and SPs, synthesize CADA analogs with enhanced drug-like properties, and establish a pharmacokinetic profile of various biologically active CADA analogs. Several CADA analogs were synthesized and investigated for their utility in photoaffinity labeling (PAL) experiments. The aryl azide CADA analog RA018 was synthesized and evaluated in PAL experiments but ultimately did not yield any labeled SP. Additionally, the synthesis of several CADA analogs with diazirines moieties was pursued and ultimately found to be unsuccessful. A series of PEGylated and mPEGylated CADA analogs were synthesized and evaluated for their biological activity and pharmacokinetic properties. These analogs exhibited better or similar potency to CADA. Finally, the pharmacokinetics of PEGylated and mPEGylated CADA analogs were analyzed alongside numerous CADA analogs that exhibit favorable biological activity and/or structural features associated with enhanced drug-like properties. ii Acknowledgements I have been extremely fortunate to be continuously surrounded by friends and family that have provided more encouragement and support than I could ever asked for. Whether they are across the globe, across the United States, or just down the hall, more people than I can possibly think have made all of this possible and I will never forget that. My advisor, Prof. Thomas. W. Bell has been absolutely instrumental in my success. I’m thankful for his patience and belief that I can do this, no matter the level of self-doubt that I brought to the table. He’s taught me how to be a great researcher, an inspiring teacher, and a good human being. I hope to follow in his footsteps in a career in academia; helping students understand chemistry, solve complex problems, and perform research to understand the absolutely fascinating ways that chemistry occurs in nature. I am grateful for his mentorship and his friendship, and I feel very fortunate to have had such meaningful conversations about everything from science to Belgian beer with him. I also want to thank my family-Doug, Lisa, Zach, and Olivia Jones, for their unwavering love and support. They haven’t ever doubted that I could complete this dissertation and I could not be more thankful for that. My grandparents, Lanny and Sandy Jones, have also been supportive in my education. Finally, my late grandparents Darryl and Jacky Larison instilled a love for the outdoors in me at an early age, which caused me to latch on to Reno upon seeing the mountains, which I am very grateful for as a place of solace and inspiration. I express my sincere thanks to my PhD committee, Dr. Ana de Bettencourt-Dias, Dr. Wesley Chalifoux, Dr. Dylan Kosma, & Dr. Ian Wallace for their guidance in both my iii qualifying exam and my dissertation. They’ve given me sound advice and guidance in my path towards becoming a better scientist and a future professor. I likely would have never pursued chemistry if it hadn’t been for the professors I had during my undergraduate studies at Concordia College. Dr. Drew Rutherford, Dr. Darin Ulness, Dr. Mark Jensen, & Dr. Darin Ulness all played crucial roles in my trajectory towards pursuing a PhD. I also express sincere thanks to Janet Thompson, who taught me how to be an effective educator. My time spent as her TA instilled a desire to pursue teaching science, which has been one of the most fulfilling experiences I’ve had in my life. I was extremely fortunate to spend time at the Rega Institute for Medical Research at KU Leuven and I want to personally thank Dr. Kurt Vermeire, Dr. Dominique Schols, and Dr. Victor Van Puyenbroeck for hosting me as a visiting scholar and teaching me so much about cotranslational translocation and biochemistry. I’ve been surrounded by a number of graduate students at UNR that have been instrumental in my success. Whether providing scientific advice or a shoulder to lean on, I want to express my deepest thanks to Korey Reid, Keveen Flieth, Dr. Rameez Ali, Dr. Truc Le, Jhonathan Brawley, Sagar Gyawali, Aziz Islam, Tyler Torres, Bill Rowley, David Ricker, Samuel Silva, and Matt Roberson. I also want to extend my sincere gratitude to several students I’ve been fortunate enough to mentor: Risa Yamane, Davison Beenfeldt, and Aubrion Franke. They were eager to help me complete my research, which was certainly helpful in completing this dissertation. However, they taught me how to teach science in a research setting, which I am extremely grateful for in my efforts towards becoming a professor. iv Finally, I want to extend my most sincere gratitude to Alexandra English, who, among pursuing her own PhD and having so many other commitments, has provided more love, support, laughter, and patience than I ever thought was humanly possible throughout this process. She inspires me to be a better scientist, a better educator, a better alpinist, and a better human. Out of all of the people who have and will ever exist, I feel so fortunate to have known Alexandra in such an exciting and difficult time in my life. Thank you for everything, Alex. v Table of Contents Abstract .............................................................................................................................. i Acknowledgements ............................................................................................................ ii List of Tables .................................................................................................................... ix List of Figures ................................................................................................................... xi List of Schemes ................................................................................................................ xx Chapter 1 .......................................................................................................................... 1 Introduction ......................................................................................................................... 2 The cluster of differentiation 4 glycoprotein, the human immunodeficiency virus, and the acquired immunodeficiency syndrome ............................................................................... 5 Current methods of HIV/AIDS therapy .............................................................................. 9 An overview of the Sec61 pathway .................................................................................. 11 Cotranslational translocation across the ER membrane: a fundamental and highly conserved process of protein expression........................................................................... 12 Inhibitors of protein translocation across the ER membrane ............................................ 16 The signal peptide-specific small molecule cyclotriazadisulfonamide (CADA) ............. 23 Mechanism of action ......................................................................................................... 23 Discovery of sortilin as a secondary substrate of CADA ................................................. 30 vi Structure-activity relationship studies between CADA analogs and hCD4 down modulation ........................................................................................................................ 32 General strategy for synthesizing CADA analogs ............................................................ 39 Summary & outlook .......................................................................................................... 42 Chapter 2 ........................................................................................................................ 44 Photoaffinity labeling: a technique for determining drug-substrate interactions.............. 45 Photophores for photoaffinity labeling experiments ......................................................... 47 Benzophenones ................................................................................................................
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